High-dose cyclophosphamide (HDC) has been shown to be an effective regimen for collecting PBPC in multiple myeloma (MM) patients, but the optimal dose to be used remains controversial. Two historical cohorts of MM patients who received G- or GM-CSF and HDC at the dose of either 7 g/m2 (HDC7, n = 74) or 4 g/m (HDC4, n = 42) were compared. As patients in the HDC4 group were more likely to have received G-CSF than GM-CSF (P < 10−3) and fewer previous alkylating agents (P = 0.004), multivariate logistic regression analysis was performed. In the HDC4 group, patients had a shorter median duration of neutropenia (P < 10−4), fewer RBC (P < 10−3) and platelet transfusions (P < 10−3) with fewer patients with platelets <20 × 109/l (P = 0.004). Moreover, fewer febrile episodes (P < 10−3) and less need of intravenous antibiotics (P < 10−3) were found in the HDC4 group. No statistical difference was observed with regard to CD34+ cell collection efficiency. Thus, the use of HDC at the dose of 4 g/m2 for the collection of PBPC in MM patients decreases hematological and extrahematological toxicity with an equivalent CD34+ cell collection efficiency. Bone Marrow Transplantation (2001) 27, 837–842.
Multiple myeloma (MM) is a B cell disorder characterized by the presence of malignant plasma cells and by a median survival not exceeding 3–4 years after conventional therapy.1 Intensive treatment with autologous hematopoietic progenitor cell support has become the treatment of choice for MM patients up to 65 years old.2
During the last decade, PBPC have progressively replaced bone marrow (BM) cells as a source of stem cells to rescue hematopoiesis after myeloablative treatments. The use of PBPC has been shown to speed up both granulocyte and platelet recovery post transplantation as compared to BM.34 High-dose chemotherapy, especially cyclophosphamide, has been shown to be effective in mobilizing PBPC.56 Despite these advantages, the optimal chemotherapy regimen for mobilization of PBPC with minimal patient inconvenience, maximal yield and low-cost profile remains to be determined. Our institution previously reported its experience of high-dose cyclophosphamide (HDC) at the dose of 7 g/m2, either alone or followed by hematopoietic growth factor (HGF) treatment, for mobilization of PBPC in 116 MM patients planned to receive subsequent autologous PBPC transplantation.7 The heavier mortality observed with increased doses might indicate that lower dosages such as 4 or 6 g/m2 are preferable.
Therefore, the aim of this study was to compare two historical cohorts of patients with MM who received HDC in the same institution either at the dose of 7 g/m2 (HDC7) (n = 74) or 4 g/m2 (HDC4) (n = 42) regimens, followed by HGF, with regard to regimen-related toxicity and CD34+ cell collection.
Materials and methods
Between August 1990 and August 1999, 116 patients with MM underwent HDC followed by HGF as mobilizing regimen either at the dose of 4 g/m2 (HDC4) or 7 g/m2 (HDC7). The diagnostic criteria for MM were those of the South West Oncology Group.8 All patients had aggressive MM defined as: (1) stage II or III MM at diagnosis according to the Durie–Salmon staging; (2) plasmacytoma or stage I MM with no response to treatment or relapse after a previous response to treatment; and (3) plasma cell leukemia. Patients were eligible for HDC if they had aggressive MM, no history of cyclophosphamide-induced cystitis, plasma creatinine levels lower than 150 μmol/l and normal hepatic and cardiac functions. None of the 116 patients had previously received high-dose chemotherapy. Previous chemotherapy regimens consisted of VAD (vincristine, doxorubicine, dexamethasone9) or a combination of standard-dose melphalan/prednisone.10
All patients received HDC treatment as mobilizing treatment and were potential candidates for high-dose chemo- or chemoradiotherapy treatment, consisting of either melphalan (HDM) (200 mg/m2) alone or a combination of HDM (140 mg/m2) and total body irradiation (8–12 Gy), followed by reinfusion of thawed PBPC. Cyclophosphamide (Endoxan; Asta Medica, Mérignac, France) was administered at the dose of either 4 g/m2 (in three consecutive 1 h infusions) or 7 g/m2 (in four consecutive 1 h infusions). Day 0 was defined as the HDC infusion day. Alkaline hyperhydration (3–4 l/m2/day i.v.) and the uroprotectant Uromitexan (Mesna, Asta Medica) were began half an hour before HDC infusion and were administered for a total of 48 h. Intravenous furosemide was used periodically to maintain a stable body weight after the initiation of HDC.
Hematopoietic growth factors
In all cases, HGF were started 24 h after HDC infusion and continued until completion of apheresis. Patients received either G-CSF (Amgen, Neuilly sur Seine, France) (5 μg/kg/day) or GM-CSF (Sandoz/Schering-Plough, Rueil-Malmaison, France) (5 μg/kg/day). All patients received sterile food and gut decontamination with non-absorbable antibiotics from day −1. When the neutrophil count was less than 0.5 × 109/l, broad-spectrum intravenous antibiotics were started at the onset of fever (38.5°C) and continued until remission of fever and neutropenia. Vancomycin and amphotericin B were added successively later in cases of persistent fever despite antibiotic administration or documented fungal infection. White blood cells (WBC) and platelet counts were monitored daily using automated counters. Irradiated prophylactic single donor platelet and red blood cell (RBC) transfusions were administered when the platelet count was less than 20 × 109/l and the hemoglobin level less than 8 g/dl, respectively. Toxicities and response criteria following HDC mobilization were evaluated according to the WHO criteria.11
PBPC collection and cryopreservation
Aphereses were planned during the recovery phase following HDC-induced aplasia and were started when the leukocyte and platelet counts showed a rise, reaching 1 × 109/l and 50 × 109/l, respectively. CD34+ cells in the peripheral blood and in the leukapheresis products were counted by flow cytometry (FACScan; Becton Dickinson, Pont de Claix, France) using direct CD34 immunofluorescence (8G12, anti-HPCA-2, conjugated either to fluorescein isocyanate, FITC or R-phycoerythrin, PE Becton Dickinson) or whole blood.12 The gated percentage of the CD34+ cell populations was multiplied by the absolute mononuclear cell number to yield an absolute CD34+ cell count. Stem cell collections were performed using a continuous flow Fenwall CS.3000 machine (Baxter, Round Lake, IL, USA). Ten litres of blood were processed at each leukapheresis. The number of aphereses was dependent on the number of CD34+ cells collected. The collection was performed daily to obtain at least 5 × 106 CD34+ cells/kg to support marrow-ablative therapy. In addition, BM was harvested under general anesthesia (at least 2 × 108 mononuclear cells/kg) if necessary. PBPC and BM cells were depleted of red blood cells and plasma by centrifugation and subsequently cryopreserved using standard techniques in 10% dimethyl- sulfoxide.13
Partial response (PR) was defined as at least a 50% reduction in serum paraprotein or greater than a 90% reduction in Bence–Jones proteinuria. Complete response (CR) required the absence of monoclonal gammapathy in serum and urine on at least 2 occasions two months apart, including the disappearance of Bence–Jones proteinuria and less than 5% of marrow plasmacytosis. Drug resistance or disease non-responsive (DR) to previous therapy was defined, as less than a 50% decrease in the M-component. Relapse was defined, according to the criteria reported by Mandelli et al,14 as follows: 25% increase in serum paraprotein level, increase in urinary paraprotein level to greater than 2 g/l, reappearance of the monoclonal component in serum or concentrated urines and increase in size or number of lytic lesions.
The median and range summarized all quantitative variables. The Mann–Whitney U and Kruskal–Wallis tests were used for comparisons between treatment groups. Chi- square and Fisher exact tests were used for comparison of categorical data. Time-to-event data were analyzed with the Kaplan–Meier estimator, and comparisons between treatment groups with logrank test in univariate analysis.15 The Cox proportional hazards regression model was used to assess which variables were associated with time to hematological recovery. The association between variables and the occurrence of toxicity was studied using a logistic regression model. We included in the multivariate analysis variables that were associated with toxicity at a threshold P < 0.10 in the univariate analysis. Our modelling strategy was based on a downward stepwise method, keeping variables that were significantly associated with toxicity at P < 0.05.15 The Statistical Application System (SAS) version 6.04 (SAS Institute, Cary, NC, USA) was used for the statistical analysis.
General description and comparison of the two groups
For the whole population, the median age at diagnosis was 55 years (range 29–74); 72 (64%) patients had stage III MM, 13 (11%) stage II MM, 28 (22%) stage I MM or plasmacytoma and three (3%) a plasma cell leukemia. The isotype of the monoclonal component was IgG in 69 cases (60%), IgA in 24 (20.5%), IgM in 11 (9%), and pure Bence–Jones protein in 12 (10.5%). At diagnosis, beta2-microglobulin levels were known for only 86 patients and ranged from 1.11 to 13.5 mg/l (median 2.75 mg/l). Thirty patients (35%) had beta2-microglobulin greater than 3 mg/l before HDC. At the time of starting HDC, 32 patients (28%) had been treated with more than one line of treatment, including an alkylating agent regimen and a VAD regimen in all cases. Before HDC, 71 patients (61%) were sensitive to previous therapy and 45 patients (39%) were considered as non-responsive.
Results of the comparison of the patient characteristics of the HDC4 and the HDC7 groups are summarized in Table 1. The median number of months from diagnosis to mobilization was significantly different between HDC4 (4.5, range 2.9–78) and HDC7 (10, range 0.9–207) (P = 0.02). A significant difference was observed with respect to alkylating agent-containing regimen use (19% vs 46%; P = 0.004) and the percentage of patients receiving more than one line of treatment (14.3% vs 35.1%; P = 0.016).
Following HDC treatment, 55 patients (74.3%) in the HDC7 group received GM-CSF and 41 patients (97.6%) in the HDC4 group received G-CSF (P < 10−3). This difference could be explained by the fact that in this historical cohort comparison, most of patients of the HDC7 group were treated between 1990 and 1995 and the majority of patients of the HDC4 group between 1995 and 1999. As clinical practice has changed over the years, G-CSF was more likely to be used during the later years. Consequently, a multivariate logistic regression analysis adjusted on the previous alkylating agent-containing regimen and type of HGF used was done to compare the results of the two groups. The response to previous therapy was not statistically different between the two groups (P = 0.304) (HDC4: CR = 7.17%, PR = 45.3%, DR = 47.6%; HDC7: CR = 4%, PR = 58.1%, DR = 37.9%). No significant differences were found for the other patient characteristics studied.
The percentages of response to HDC were not statistically different between the two groups (P = 0.107) (HDC4 n = 41: CR = 9.7%, PR = 56.1%, DR = 34.2%; HDC7 n = 71: CR = 9.8%, PR = 73.2%, DR = 16.9%), even if HDC7 tended to give best results.
Hematopoietic recovery and supportive care after HDC
Four patients died after HDC, two (one in each group of treatment) during the aplastic phase (both from septic shock) and two after hematologic recovery (both in the HDC7 group), one from septic shock and another from cardiac failure.
After HDC, for the whole population, the median times post HDC to achieve more than 0.5 × 109 granulocytes/l and more than 20 × 109 platelets/l were 13 days (range 6–48) and 11 days (range 0–37), respectively. Whilst all patients of the two groups became neutropenic, by Kaplan–Meier analysis, HDC4 patients had a shorter median duration of neutropenia (less than 0.5 × 109 granulocytes/l) (10 vs 14 days; P < 10−4) (Figure 1). Moreover, only 28.6% of HDC4 patients had a thrombopenia lower than 20 × 109/l platelets compared to 75.7% in the HDC7 group (P < 10−4) (Table 2). Therefore, the percentage of patients receiving prophylactic platelet and RBC transfusions was lower in the HDC4 group than in the HDC7 group (26.2% vs 75.7%; P < 10−3) and (52.4% vs 94.6%; P < 10−3), respectively.
These results were also confirmed by multivariate logistic regression analysis (Table 3). The number of patients who had platelet counts lower than 20 × 109/l after HDC was still statistically lower in the HDC4 group. For those patients the duration of thrombopenia (platelets <20 × 109/l) was not different between the two groups. A multivariate Cox analysis was also performed to analyze the effect of HDC dosage on neutrophil recovery adjusted on the type of HGF use and previous use of an alkylating-agent containing regimen, and confirmed the statistically significant difference between the two doses of HDC (P = 0.02, relative risk = 1.83).
Extrahematologic toxicity after HDC
In univariate analysis, during marrow aplasia, 103 patients experienced fever ⩾38.5°C (31 in the HDC4 group and 72 in the HDC7 group). HDC4 entailed fewer febrile episodes (73.8% vs 97.3%; P < 10−3) and less use of intravenous antibiotics (69.1% vs 97.3%; P < 10−3) than HDC7. The median number of days of intravenous antibiotics used was also lower with HDC4 compared to HDC7 (5 vs 10) (P < 10−4) (Table 2).
Moreover, by multivariate logistic regression analysis adjusted on previous use of alkylating agents and type of HGF, the lower number of febrile episodes (odds ratio = 0.06 (95% CI, 0.004–1.08); P = 0.05) and the lesser use of intravenous antibiotics (odds ratio = 0.82 (95% CI, 0.70–0.97); P = 0.02) in the HDC4 group was confirmed (Table 3).
The median duration of hospitalisation was shorter (15 vs 22 days) (P < 10−4) in the HDC4 group, as was the median time between HDC treatment and first leukapheresis (11 vs 16 days) (P < 10−4) (Table 2). These results were not confirmed by multivariate analysis.
Moreover, there was no statistically significant difference between the two groups in terms of grade III–IV mucositis, grade III–IV hemorrhagic cystitis, grade I–II renal insufficiency or microbiologically documented infection (Table 2).
PBPC mobilisation and collection
For 10 patients, PBPC collection could not be performed for several reasons: death before collection from septic shock (n = 3) or acute cardiac failure (n = 1), bacteremia (n = 1), liver toxicity (n = 1), myocardiopathy (n = 1), thromboembolism (n = 1), and persistent low blood counts (n = 2).
For the remaining 106 patients, a median number of six aphereses (range 1–7) was performed. Apheresis began between day 7 and day 36 (median day 14) following HDC treatment. The median day post HDC of first leukapheresis was significantly earlier in the HDC4 group (day 11, range 9–27) than in the HDC7 group (day 16, range 7–36) in both univariate (P < 10−4) and multivariate analysis (P = 0.02). The median number of aphereses performed in each group was three (range 1–7) in the HDC4 and six (range 2–7) in the HDC7 group (P < 10−4). The median number of CD34+ cells collected per patient was 13.4 × 106/kg (range 0.7–66.8) in the HDC4 group and 8.6 × 106/kg (range 0.4–166) in the HDC7 group. The proportion of patients who had more than 2.5 × 106/kg CD34+ cells in apheresis products was higher in the HDC4 group (92.8%) than in the HDC7 group (67.6%) (odds ratio = 1.59 (95% CI, 0.11–23.9); P = 0.74) (Table 3). BM harvest was required for only one patient in the HDC4 but for eight patients in the HDC7 group.
HDC has a broad spectrum of antitumor activity and considerable efficacy even on refractory or relapsing tumors. When used in patients not extensively pre-treated and in association with 2-mercapto-ethane-sulphonate (Uromitexan) to prevent urothelial toxicity,16 very high doses up to 7 g/m2 are surprisingly well tolerated. In this favorable clinical setting, its use is mainly limited by the risk of severe life-threatening infections and by frequent thrombocytopenias requiring platelet support.
At the present time, the optimal method for the mobilization of PBPC with the minimal patient inconvenience, maximum yield and lowest cost profile remains controversial.17 In steady-state, few PBPC can be harvested from peripheral blood in such patients. Much larger yields can be obtained during hematopoietic recovery after myelosuppressive therapy or after administration of HGF as recently reported in a randomized cross-over trial by Koç et al.18 Some authors have found HDC at 7 g/m2 to be the optimal regimen but infectious and long-lasting thrombocytopenia have been observed in numerous patients.1920 Other authors have used HDC at lower doses (4 g/m2) associated with HGF in MM patients, and have observed adequate collection of PBPC and less severe complications.212223 Despite the empirical use of this strategy, the optimum schedule for PBPC mobilization in MM patients remains controversial.
In this report, we confirm that an intermediate dose of cyclophosphamide (4 g/m2) combined with G- or GM-CSF is an efficient and safe mobilizing regimen in MM patients as compared with the use of cyclophosphamide at the dose of 7 g/m2. Hematological toxicities such as neutrophil recovery, thrombocytopenia, RBC and platelet transfusions were less extensive in the HDC4 group, as were requirements for intravenous antibiotics. Our results are concordant with those in previous studies: in a historical series of 32 MM, Goldschmidt et al24 found longer durations of severe neutropenia (P = 0.0015) and thrombocytopenia (P = 0.036) in patients mobilized by HDC at the dose of 7 g/m2 than in those mobilized by HDC at the dose of 4 g/m2. Rowlings et al20 reported for 59 patients with advanced cancers that 7 g/m2 is associated with a significant increase in hematological and non-hematological toxicities. In a population of 60 patients with various diseases (22 lymphoma, five Hodgkin's disease; 6 MM, 17 breast carcinoma and 10 other advanced malignancies), Kotasek et al19 also found that patients receiving HDC at the dose of 7 g/m2 had significantly longer neutropenic (median = 10 vs 6.6 days, P = 0.0001) and thrombocytopenic nadirs (median = 7 vs 1.4 days; P = 0.0001) than those receiving HDC at the dose of 4 g/m2. The depth of the leukocyte and the platelets nadirs was also significantly different. Patients mobilized using the 7 g/m2 dosage had significantly lower leukocyte and platelet nadirs. Febrile episodes (⩾38.5°C) requiring intravenous antibiotics were noted in 21% of the patients receiving HDC at the 4 g/m2 dosage but were present in 100% of those mobilized with the 7 g/m2 dosage. A significant difference was found in the mean duration of fever (P = 0.01). Surprisingly, in this study, the median duration of hospitalization after HDC did not differ between the two groups.
Regarding PBPC collection in our study, the total number of CD34+ cells collected in two groups was equal and our results differ slightly from previous studies. Indeed, other studies have reported that an increase in the cyclophosphamide dose results in an increase in the number of PBPC harvested.1924 Kotasek et al,19 in a prospective trial, showed that administration of 7 g/m2 HDC resulted in statistically significant higher peak values for CD34 progenitor cells in the peripheral blood and then, a better collection than in a group receiving HDC at the dose of 4 g/m2. It is difficult to compare these results to those of our study as no patient of the Kotasek study received HGF after HDC. In another study Goldschmidt et al24 analyzed the impact of dose of cyclophosphamide (4 vs 7 g/m2) associated with G-CSF in 32 successive patients with MM. A statistically significantly higher peak value for CD34+ progenitor cells in the peripheral blood was reported resulting in the mean number of CD34+ cells/kg per leukapheresis was significantly increased in the HDC7 group (P = 0.029). However, as in our study, no significant difference for the number of patients with ⩾2.5 × 106 CD34+ cells collected was observed between the two groups. Our results could not be explained by the characteristics of the two groups which were different in terms of type of HGF used and previous use of alkylating agents as multivariate analysis adjusted on these parameters showed the same results. Moreover, different studies performed in our institution or by others had shown that the type of HGF used in association with HDC (either 4 or 7 g/m2) has no impact on the collection of PBPC.6725 For these reasons, we restricted the analysis to the population who received only G-CSF after the HDC. No difference in terms of CD34+ cells collected was found in favor of a HDC group (P = 0.74).
The aim of our study was to evaluate the toxicities observed in two groups of patients with aggressive MM, receiving cyclophosphamide at the dose of either 4 or 7 g/m2. To our knowledge, these 116 patients constitute the largest monocentric series in which two levels of cyclophosphamide dose are compared. This retrospective study does have some limitations because there were two historical cohorts who were not treated in the same period and treatments given before mobilization were different with fewer alkylating agents in the HDC4 group. However, the different toxicities were comparable with statistical analysis adjusted on this parameter, and HDC4 was found to be better tolerated and able to mobilize enough PBPC without losing any antitumor activity.
In conclusion, HDC 4 g/m appears to be an efficient procedure for PBPC collection in high-risk MM patients with reduction of the different hematological toxicities when compared to HDC 7 g/m2. For patients with prior exposure to melphalan, a known risk factor for mobilising sufficient progenitor cells,2627 a combination of several cytokines such as SCF and G-CSF after HDC4, as demonstrated by Facon et al,27 can achieve successful collection in heavily pretreated patients and could be an alternative regimen.
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We are grateful to Mr Cook for the careful review of the manuscript.
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Fitoussi, O., Perreau, V., Boiron, J. et al. A comparison of toxicity following two different doses of cyclophosphamide for mobilization of peripheral blood progenitor cells in 116 multiple myeloma patients. Bone Marrow Transplant 27, 837–842 (2001) doi:10.1038/sj.bmt.1702879
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