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© 2000 American Society for Clinical Oncology Randomized Trial of Bone Marrow Versus Lenograstim-Primed Blood Cell Allogeneic Transplantation in Patients With Early-Stage Leukemia: A Report From the Société Française de Greffe de MoelleFrom the Société Française de Greffe de Moelle, Lyon, France. Address reprint requests to Didier Blaise, MD, Unité de Transplantation et de Thérapie Cellulaire, Institut Paoli Calmettes, 232 Bd Ste Marguerite, 13273 Marseille Cedex 9, France; email blaised@ marseille.fnclcc.fr.
PURPOSE: To compare hematologic recovery in patients receiving allogeneic blood cell transplantation (BCT) with those receiving allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS: One hundred eleven patients with leukemia in the early stages and with HLA-matched sibling donors were randomized in this study. One hundred one underwent transplantation. Standard procedures for collection and transplantation were used. Patients did not receive prophylactic granulocyte colony-stimulating factor after undergoing transplantation. In addition to clinical end points being established, a prospective and comparative economic evaluation of the first 6 months after transplantation was performed. RESULTS: Groups were balanced for patient, donor, and transplant characteristics. Blood cell collection led to the collection of a higher number of CD34+ and CD3+ cells than did bone marrow collection (P < 10-6) without reported side effects for the donor. Patients in the BCT group reached platelet counts of 25 and 50 x 109 platelets/L 8 and 11 days earlier than did the BMT group (P < 10-4 and P < 10-5), respectively. This resulted in fewer platelet transfusions during the first 180 days after transplantation (P = .002) for the former group. The time to reach neutrophil counts of 0.5 and 1 x 109 neutrophils/L was 6 and 7 days shorter, respectively, in the BCT group than in the BMT group (P < 10-5). This quicker hematologic recovery was associated with a shorter length of hospitalization and a decrease in total cost of procedure during the first 6 months. CONCLUSION: This study establishes that allogeneic BCT results in quicker hematologic recovery but is associated with a higher occurrence of chronic graft-versus-host disease.
BLOOD CELL transplantation (BCT) is now the standard for autologous transplant,1 mainly because it affords easier progenitor collection, quicker hematologic recovery, and a decrease in related cost.2-4 Although it would be of great interest to learn whether these same advantages could be reproduced using the allogeneic method, because of potential drawbacks more information is needed before this new procedure can be widely adopted. First, although stem-cell collection without general anesthesia is particularly valuable in healthy donors, this value has to be balanced with the need for granulocyte colony-stimulating factor (G-CSF) as a mobilizing agent and the potential long-term deleterious effects of G-CSF in healthy individuals.5 Second, although infusing more progenitors may shorten hematopoietic recovery and decrease morbidity and costs, it implies the reinfusion of a larger number of immunocompetent cells. This may be effective in provoking a more potent antitumoral effect but may also increase the risk of graft-versus-host disease (GVHD). Early reports have assessed the short-term feasibility of allogeneic BCT and have provided preliminary answers to some of these problems, notably showing the probability of platelet recovery.6-8 We recently established the feasibility of allogeneic BCT after the priming of HLA-identical healthy sibling donors with a recombinant human (rhu) G-CSF (lenograstim) in a pilot study9 and documented the high quality of engraftment.10 In addition, a cost advantage was found for BCT patients compared with historical bone marrow transplantation (BMT) controls.11,12 In 1996, a study comparing allogeneic BCT in patients with advanced hematologic malignancies with historical BMT controls also suggested quicker hematologic recovery.13 However, the superiority of BCT over BMT in allogeneic situations for hematologic recovery has not yet been definitively established. For these reasons, the centers affiliated with the Société Française de Greffe de Moelle (SFGM) decided in 1996 to conduct a randomized trial prospectively comparing allogeneic BCT and allogeneic BMT in terms of platelet recovery. In addition to this primary question and to the comparison of overall hematologic recovery and outcome, this study was designed to prospectively evaluate the cost of transplantation during the first 6 months after the two procedures. We report here the results of this trial showing that BCT allows quicker platelet and neutrophil recovery but is associated with increased chronic GVHD occurrence.
Study Design This was a multicenter, randomized comparative trial performed between September 1996 and October 1998 in 17 centers affiliated with the SFGM. The protocol was approved by the scientific board of the SFGM and the local ethical committee (Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale of Marseille 2). All procedures were performed after written informed consent was obtained from the recipients and donors. When the transplantation was scheduled, the attending physician contacted the trial data manager by fax. Randomization was expected to be performed no earlier than 1 month before the transplantation. However, to minimize the bias introduced by the eventual exclusion resulting from adverse events occurring between randomization and transplantation, the data manager randomized each new patient using a minimization method that allowed the more likely randomization of future patients to one arm if previous patients failed to receive a transplant in this arm. With the stratification of center and diagnosis, the purpose of this method was to assure a balance between the two groups and to minimize the variations resulting from different practices in terms of supportive care or transfusions. Data were collected every 30 days by two coordinating centers (Institut Paoli Calmettes, Marseille, and Hopital Henri Mondor, Créteil) and entered onto the same database. This study was designed to detect a 10-day reduction in the time to reach 25 x 109 platelets/L. Data from a historical control group of patients treated with BMT indicated that 50 patients per group were necessary to detect this difference between the two groups (one-tailed alpha probability = 0.05; beta power = 80%). An interim analysis performed in September 1998 on the first 57 patients showed that the primary objective was already achieved. It was decided, however, to complete the trial to analyze secondary end points such as the occurrence of acute and chronic GVHD. On October 1, 1998, 111 patients were randomized, and in May 1999, all data were reviewed. One hundred one patients (91%) finally proceeded to transplantation.
Study End Points
Patient Eligibility
Treatments Graft collection and reinfusion. The day of cell infusion was designated as day 0. In the BCT group, mobilization consisted of daily subcutaneous administration of lenograstim at the dose of 10 µg/kg. Treatment started on day -5 and ended on day -1. Per protocol, the collection of at least 4 x 106 CD34+ cells/kg in two or three (maximum) cytaphereses was sought. The first cytapheresis was performed on day -1, and cells were kept overnight at 4°C and reinfused on day 0 with the cells from the second cytapheresis. If necessary, the third cytapheresis was performed and cells were infused on day 1 after one more injection of lenograstim to the donor on day 0. In the BMT group, a collection of at least 2 x 108 nucleated cells/kg was requested and autologous blood transfusion was usually performed. In both groups, cells were collected and processed according to the standard procedures of each center, and the whole collection was reinfused. According to the current practice in France, prophylactic G-CSF after transplantation was not allowed per protocol in either of the two groups. GVHD prophylaxis. All patients received postgraft immunosuppression consisting of short methotrexate (on days 1, 3, and 6) and cyclosporine.18 Cyclosporine was started intravenously on day -1, usually at the dosage of 2 to 3 mg/kg, and switched to all oral formulation as soon as oral intake was satisfactory. The dosage was adapted to blood levels and renal function according to each center’s practice. Both acute and chronic GVHD were evaluated according to usual gradation.19-21 Concerning chronic GVHD, the maximum stage during the overall follow-up was taken into account. Supportive care. Patient management was performed according to the standard procedures of each center and was expected to be the same in the two different groups for a given center. In particular, posttransplantation G-CSF was not systematically allowed and was restricted (notably for patients who did not reach 0.5 x 109 neutrophils/L by day 21) according to the decision of the attending physician in each situation. Immunophenotyping. In both groups, each graft was analyzed in terms of nucleated cells, hematopoietic progenitors (CD34+ cells), and lymphoid subpopulation (CD3+ cells) by flow cytometry using standard procedures in each center.
Economic Evaluation Monetary values were attributed to each of these quantities on the basis of unit costs (average 1998 French prices). The total yearly cost of consumable supplies, hotel cost (food and laundry costs), personnel cost, and depreciation of equipment (for 5 years) were measured to calculate a per diem cost for each stay in the transplantation unit or in the hematology unit (room cost) and each visit to the outpatient clinic. The step-down method was used to calculate the overheads of these two unit costs.22 Drug costs were the average purchasing prices observed in the French Regional Centers for Cancer Research and Treatment. Transfusion costs were the official 1998 French prices established each year through direct government regulation. The laboratory tests, as well as the TBI costs, were evaluated using the prices of medical technical acts, which are established at the national level by the Sickness Fund of the French Social Security. Collection costs were also included in the analysis. Apheresis and bone marrow collection costs, already measured in a prior study, were used.23 However, the blood cell collection cost was specifically computed for each donor according to the number of aphereses and the administered quantity of G-CSF. Additional costs resulting from blood autotransfusion in the BM group, as well as hospitalizations and visits to outpatient clinics, were also calculated in both groups.
Statistics
In both groups, patient and donor characteristics were balanced, notably for prognosis factors of GVHD (Table 1). There was a median age (± SD) of 37 ± 8 years and a sex ratio of 60 males to 51 females. Seventy-three patients (66%) were treated for acute myeloid leukemia (n = 50) or ALL (n = 23), of whom 66 (90%) were in first complete remission. Thirty-eight patients (34%) were diagnosed with CML in first chronic phase. All donors (median age ± SD, 37 ± 10 years; sex ratio, 59 males to 52 females) were HLA-A–, HLA-B–, and HLA-DR–matched siblings.
Ten patients did not proceed to transplantation because of early relapse (Table 1). For the 101 remaining patients, the time between randomization and transplantation was 32 days (range, 15 to 132 days) and 30 days (range, 7 to 79 days) in the BCT and BMT groups, respectively (P = not significant [NS]). Graft collection was satisfactory in both groups according to standard practice. A median of two (range, one to three) cytaphereses was performed (one cytapheresis, n = 6; two cytaphereses, n = 36; three cytaphereses, n = 6). All 53 bone marrow donors were admitted for the collection procedure compared with only 13 of 48 blood cell donors (P < .001), who were hospitalized because of the distance between home and the clinic. The median duration of hospitalization was 3 days (range, 1 to 6 days). None of the donors in the BCT group had central venous lines inserted, and no donor in the BMT group received an allogeneic blood transfusion during or after bone marrow collection. At the time of analysis, no other serious side-effects were reported for any of the 101 donors. As expected, a significantly greater quantity of nucleated cells, CD34+ hematopoietic progenitors, and lymphoid cells were obtained by peripheral collection and reinfused (Table 2). Two patients lacked engraftment (BCT, n = 1 [death on day 26 {sepsis}]; BMT, n = 1 [death on day 9 {veno-occlusive disease}]), whereas the platelet counts of seven individuals never reached 25 x 106 platelets/L (CSP, n = 2 [deaths on days 46 and 188 {GVHD}]; BMT, n = 5 [deaths on days 30 {sepsis}, 46, 48, 102, 119, and 159 {GVHD}]). Platelet counts of patients in the BCT group reached 25 x 109 platelets/L 8 days earlier than did those in the BMT group (P < 10-4) (Table 2; Fig 1). This difference increased to 11 days for the end point of 50 x 109 platelets/L (P < 10-5), which led, in turn, to a shorter time period to reach platelet transfusion independence (12 v 18 days; P < 10-4) and to fewer platelet transfusions during the first 180 days after transplantation (three v six transfusions; P = .002). Ninety-five patients (94%) achieved neutrophil recovery without any G-CSF support. However, six patients (BCT, n = 2; BMT, n = 4; P = NS) were treated with lenograstim before reaching a neutrophil count of 0.5 x 109 neutrophils/L, starting on a median of day 17 (range, day 5 to 25) with a duration of 12 days of G-CSF administration (range, 4 to 20 days). In three cases, G-CSF was started early during a septic episode on days 5, 12, and 14 (BCT, n = 2; BMT, n = 1). In the three other cases, G-CSF was administered because the attending physician believed that the neutrophil recovery was slow (on days 19, 21, and 25: all BMT). Median time to reach a neutrophil count of 0.5 and 1 x 109 neutrophils/L was 6 and 7 days shorter in the BCT group (P < 10-5 and P < 10-5), respectively (Table 2; Fig 1). For all other hematologic parameters studied during the first 6 months, the kinetic of engraftment was quicker in the BCT group (Table 2). The number of CD34+ cells reinfused significantly influenced the number of days to reach 0.5 x 109 neutrophils/L (r = -.504; P < 10-6) and 25 x 109 platelets/L (r = -.566; P < 10-6). The correlation persisted for neutrophils and platelets when analysis was restricted to the BCT population (neutrophils: r = -.281, P < .05; platelets: r = -.332, P < .02) but only for platelets in the BMT group (r = -.330; P < .05).
Patients in the BCT group were discharged sooner and were not rehospitalized more often than were those in the BMT group (Table 2). In fact, 15 (33%) of 46 patients in the BCT group and 26 (50%) of 52 in the BMT group (P = NS) were rehospitalized for a median duration of 12 days (range, 3 to 44 days) and 17 days (range, 2 to 89 days), respectively (P = NS). Forty-three patients developed grade 2 or higher acute GVHD, with no difference between the two groups (BCT, 44%; BMT, 42%) (Fig 2). Conversely, 39 patients developed chronic GVHD with substantial differences between the two groups (Table 3): GVHD occurred more often (24 [50%] of 48) and was more severe in the BCT group than in the BMT group (15 [28%] of 53; P < .03) (Fig 2). Ten patients (BCT, n = 6; BMT, n = 4; P = NS) presented chronic GVHD without any previous acute GVHD, whereas nine others (BCT, n = 7; BMT, n = 2; P = NS) did so after having grade 1 acute GVHD. Six patients experienced onset of de novo chronic GVHD after 6 months (BCT, n = 4 [at 8, 9, 10, and 12 months]; BMT, n = 2 [at 8 and 12 months]).
In this series of patients, chronic GVHD had a major effect on relapse control: only one patient relapsed of the 39 who experienced chronic GVHD, compared with seven of the 55 assessable patients without (2-year relapse estimate by using landmark analysis,28 excluding patients who died or relapsed before day 100: 4% [range, 1% to 18%] v 18% [range, 9% to 34%]; P < .03). This effect persisted when the analysis was restricted to the BCT population (patients with chronic GVHD: zero relapses in 24 patients; patients without chronic GVHD: three relapses in 20 patients [2-year relapse estimate: 22% {range, 7% to 51%}]; P < .04). However, this did not equate into a clear survival advantage. With a median follow-up of 20 months (range, 6 to 35 months), nine patients (9%) relapsed at a median of 7 months (range, 2 to 17 months) after transplantation, with no difference between the two groups (Fig 3). Overall, 31 patients died at a median of 5 months (range, 0.5 to 19 months), with no difference between the two groups. Eleven patients in each group (BCT, 23%; BMT, 21%) died without relapse before day 180 (P = NS). Nine patients died from relapse (BCT, n = 3; BMT, n = 6), 15 patients from GVHD (BCT, n = 6; BMT, n = 9), two from interstitial pneumonitis (BCT, n = 1; BMT, n = 1), two from venous occlusive disease (BCT, n = 1;BMT, n = 1), two from sepsis (BCT, n = 2), and one from a car accident (BCT, n = 1). Two-year overall survival and LFS probabilities reached 66% (range, 56% to 75%) and 67% (range, 56% to 76%), respectively, with no statistical difference between the two groups. Considering the intent-to-treat analysis, the 2-year probabilities for BCT (n = 55) and BMT (n = 56) were respectively 61% (range, 47% to 74%), respectively, and 61% (range, 47% to 74%) for survival (P = NS) and 58% (range, 44% to 71%) and 62% (range, 48% to 74%), respectively, for LFS (P = NS).
Economic results are presented in Table 4. Patients treated with BCT presented a 16% decrease in the total cost of the first 180 days (P = .004), although graft collection costs were significantly higher. Stimulation with hematopoietic growth factor (mean ± SD, 1,494 ± 290 euros) represented 54% ± 9% of the blood cell collection cost. The overall difference was mainly a result of the lower room cost in the BCT group (20%; P = .01), which represents 48% of the total cost in both groups. A substantial decrease in the cost of platelet transfusion (P = .004), laboratory tests (P = .04), and drugs (P = .022) emphasizes this difference.
This randomized study is the first to prospectively establish that allogeneic BCT leads to a quicker neutrophil and platelet recovery than does BMT. For all studied parameters (time to reach 0.5 or 1 x 109 neutrophils/L, time to reach 25 or 50 x 109 platelets/L, time to platelet independence, and number of platelet transfusions), the differences between the two groups were highly significant. Schmitz et al29 recently reported an interim analysis of a study comparing filgrastim-primed allogeneic BCT and BMT that suggested more limited differences in hematologic recovery between the two groups. However, in the study of Schmitz et al, all patients were treated with posttransplantation G-CSF, which may minimize the difference in neutrophil recovery between BCT and BMT. The use of G-CSF after transplantation is not, however, the common practice in France, in part because of uncertainty concerning the impact on residual leukemia and because a deleterious effect on platelet reconstitution after transplantation cannot be ruled out.30 Moreover, the CD34+ cell differential between blood cell and bone marrow graft composition is lower in the study of Schmitz et al (6.7 v 4.0, for a difference of > 70%) than in ours (6.6 v 2.4, for a difference of > 175%) and may partly explain the lower differential in hematologic recovery. In our study, quicker hematologic recovery in the BCT group led to a decrease in the length of initial hospitalization (35 v 40 days; P = .03). This was not associated with an increased rehospitalization afterward. Our study also establishes that the reinfusion of a 10-fold increase in the number of mature T lymphocytes does not lead to an increase in the incidence or severity of acute GVHD in the BCT population, as suggested in some historical comparisons.13,31 We have also established that BCT is associated with more frequent and severe chronic GVHD, as was previously suspected.9,32-34 On the other hand, we confirm the antileukemic effect of chronic GVHD, an effect maintained in the BCT setting. Thus, it is important not to dissociate the evaluation of chronic GVHD from the evaluation of relapse and survival, because they clearly interact.35 In other words, allogeneic BCT cannot be rejected only on the argument of an increased incidence of chronic GVHD: its severity and its final impact on relapse and survival have to be assessed. To be conclusive, however, future studies will require larger populations and longer follow-up of randomized studies. Finally, the impact of G-CSF priming on T-cell functions36 and on alloreactivity for both graft-versus-host and graft-versus-leukemia effects remains unclear and requires further study.37 A major concern in hematopoietic stem-cell transplantation is the risk undertaken by donors. These healthy individuals provide a voluntary donation for a family member. Even if this donation does not jeopardize their hematopoietic future, the collection procedure remains a real problem. Bone marrow collection usually requires general anesthesia and multiple bone punctures and is not devoid of the possibility of serious accidents.38 Although blood cell collection does not suffer from such drawbacks, immediate complications are possible,39-41 and the long-term impact of several days of recombinant G-CSF is still debated.5 In our study, no severe adverse effect has so far been recorded. That the best procedure remains undetermined indicates the need for long-term follow-up of all volunteer donors. This is presently ongoing for the patients entered onto this study. Finally, this study is the first to prospectively compare, in terms of real direct medical costs, allogeneic G-CSF–primed BCT with allogeneic BMT. Although the evaluation of absolute costs cannot be totally extrapolated for other countries or health systems (notably the United States), it is worthwhile to note that BMT cost estimation remains in the same range as those in previous European studies.42-46 However, the comparison, based on clearly defined events, should remain valuable. Decreased length of hospitalization and transfusion requirements associated with better hematologic recovery in the BCT group offset the increased cost resulting from the use of G-CSF for collection, which led to a significant decrease in total costs as already shown in the autologous situation.4 Because of the known problem of differences between hospital charges and real costs,47 especially in the context of publicly funded health care systems such as that of the French, we chose to evaluate costs of the clinical units on the basis of a detailed observation of all consumed resources in physical quantities. Although the methodology has been previously validated on several cohorts of patients in mono- and multicenter studies, as well as in the auto- and allogeneic setting,2,4,11,12 our cost analysis retains certain deficiencies: some costs are clearly underestimated (radiologic investigation, cost of intensive care hospitalization, and costs related to the donors’ time off from work). Furthermore, analysis was limited to the first 6 months, which represents only a part, although a major one, of the costs of the whole procedure.48 However, considering the items taken into account for each procedure and the accurate assessment of the unit costs, we are confident that no major omissions exist that would greatly alter the cost comparison between the two procedures in the first 6 months. Thus, the use of G-CSF for priming allogeneic blood cells, leading to improved hematopoietic reconstitution, does not contribute to an increase in early expenses during the first 6 months of transplantation but rather to a decrease. It can therefore be argued that economic objections cannot be used to reject this procedure. Longer follow-up would be necessary, however, to assess the respective costs resulting from the length of chronic GVHD therapy as well as from relapse treatment, two events which are inversely associated. On the basis of these data, we conclude that allogeneic BCT leads to a dramatic improvement in both platelet and neutrophil reconstitution. However, this benefit is associated with the occurrence of more severe chronic GVHD. Although our data concerning the impact of chronic GVHD on leukemic control may prompt the consideration of allogeneic BCT for patients presenting high-risk leukemia, longer follow-up is required to definitively assess the impact of chronic GVHD on outcome for both relapse and quality of life. Concerning patients with a low-relapse risk, the benefit of a quicker hematologic recovery must be balanced with the risk of severe chronic GVHD and, consequently, deserves further investigation.
Supported in part by a grant from the French Ministry of Health (Programme Hospitalier de Recherche Clinique 1996) and a grant from the Ligue Nationale de Lutte Contre le Cancer. Laboratoires Rhône-Poulenc Rorer (Montrouge, France) provided some support for this study but did not participate in either the definition or data analysis. We thank D. Maraninchi, MD, and N.Vey, MD, for extensive and helpful review of the manuscript; V.-J. Bardou, MD (Institut Paoli-Calmettes, Marseille), and A.G. Lecoroller, PhD (INSERM Unit, U379, Marseille), for help with statistical analysis; and Valerie Cailleton (INSERM U379, Marseille) and Joelle Beaune (Hopital Henri-Mondor, Créteil) for data processing. We also thank the following members of the SFGM for their active participation: F. Guilhot (Poitiers), N. Fégueux (Montpellier), J.J. Sotto (Grenoble), M. Legros (deceased; Clermont Ferrand); N. Ifrah (Angers), and D. Guyotat (St Etienne).
D. Blaise, M. Kuentz, and M. Michallet contributed equally to this work.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
18 years. HLA typing was determined serologically for the A and B loci and molecularly for the DR locus. In addition, patients had to satisfy the common clinical and biologic criteria usually required to receive an allogeneic transplantation. 
2 test corrected with the Yates method, if necessary. The correlation between two numeric variables was studied using the Spearman rank correlation test. The primary factor analyzed was the time to reach 25 x 109 platelets/L without any platelet transfusion during a 5-day period. The probability of this parameter and of other hematologic recovery parameters was expressed by calculating the cumulative incidence (CI) curves, with death as a competing risk.
