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Kinetics of Peripheral Blood Stem Cell Mobilization Following G-CSF-Supported Chemotherapy RUTH SEGGEWISS,a EIKE CHRISTIAN BUSS,a DORIS HERRMANN,b HARTMUT GOLDSCHMIDT,a ANTHONY DICK HO,a STEFAN FRUEHAUFa a
Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; b Cytonet Heidelberg GmbH, Transplantation Laboratory, Heidelberg, Germany
Key Words. Mobilization kinetics · Peripheral blood stem cell collection · CD34+ · Poor mobilizer · Premobilization therapy
A BSTRACT It would be a clinical and economical advantage if the optimal time point of peripheral blood stem cell (PBSC) mobilization following G-CSF-supported chemotherapy (CT) was known in advance. Therefore, we retrospectively analyzed mobilization parameters in 113 adult tumor patients treated in our institution within 1 year. The start of apheresis was guided by CD34+ cell measurements in the PB and occurred on or after day 11 after start of mobilization CT in 97% of patients. The median peak (p)CD34+ cell count in PB uniformly occurred on day 14-15 (range: 6-32 days) after the start of CT, irrespective of the diagnosis (multiple myeloma
n = 76, other histology n = 37), the type, but not the amount, of premobilization CT or radiotherapy (RT), the mobilization regimen, or the G-CSF dosage administered. Among more heavily pretreated patients (>six cycles of prior CT or RT), a higher proportion mobilized late (pCD34+ cell count later than day 20 in 12% and 13%, respectively, versus 2%-5% in the other groups). Therefore, we propose to start measuring CD34+ cells in the PB on day 11 after the start of mobilization therapy. The wide range of optimal mobilization time points argues for an individualized rather than a preset start of apheresis. Stem Cells 2003;21:568-574
INTRODUCTION High-dose chemotherapy (CT) or radiotherapy (RT) requiring autologous hematopoietic stem cell support is frequently performed in a variety of malignant disorders, like multiple myeloma, acute leukemia, and lymphoma [1]. Peripheral blood stem cells (PBSCs) collected after the administration of CT and colony-stimulating factors, such as G-CSF, are the preferred source of stem cells, as hematopoietic reconstitution is more rapid than with autologous bone marrow so that fewer blood or platelet transfusions are needed [2, 3]. Furthermore, PBSCs can be harvested without the use of general anesthesia. Studies
were conceived and are in progress to determine the optimal mobilization regimens that will permit the achievement of the necessary CD34+ cell thresholds with only one or two aphereses [4-6]. Following G-CSF-supported mobilization CT, CD34+ cell harvests may differ interindividually by more than 100-fold [7, 8]. In this retrospective study, we analyzed predictive factors for the time points of PBSC collection in 113 tumor patients. As more and more patients are treated under outpatient conditions due to more experience with the procedure and increasing socioeconomic constraints, we wanted to evaluate whether it is possible to predict the optimal time point of PBSC harvest. The aim of
Correspondence: Stefan Fruehauf, M.D., Department of Internal Medicine V, University of Heidelberg, Hospitalstr. 3, 69115 Heidelberg, Germany. Telephone: 49-6221-562781; Fax: 49-6221-565722; e-mail:
[email protected] delberg.de Received March 17, 2003; accepted for publication May 23, 2003. ©AlphaMed Press 1066-5099/2003/$12.00/0
STEM CELLS 2003;21:568-574
www.StemCells.com
Seggewiss, Buss, Herrmann et al. this retrospective analysis was to identify parameters for a successful, efficient, and economical PBSC collection.
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VIDE (vincristine 1.5 mg/m2/d day 1, ifosfamide 3,000 mg/m2/d days 1-3, doxorubicin 20 mg/m2/d days 1-3, etoposide 150 mg/m2/d days 1-3, n = 1).
MATERIALS AND METHODS Patients PBSCs were mobilized with CT followed by G-CSF, both to reduce the tumor burden and to facilitate PBSC harvesting. One hundred thirteen patients (median age: 56 years, range: 19-69) were mobilized with 18 different CT regimens and s.c. G-CSF-administration (2.8-15 µg/kg body weight [bw], G-CSF started 1 or more days after completion of CT and continued until completion of PBSC collection) in the year 2001. Seventy-six patients had multiple myeloma (MM) or other malignancies (10 amyloidosis, one acute lymphocytic leukemia [ALL], one acute myeloid leukemia [AML], 18 non-Hodgkin’s lymphoma [NHL], six Hodgkin’s disease, one Ewing’s sarcoma). The choice of mobilization regimens was made according to disease-specific protocols and according to the tumor status. Mobilization Regimens Drugs and dosages used were: ifosfamide (4,000 mg/m2/d days 1-3, n = 5), cyclophosphamide (2,000 mg/m2/d days 1-2, n = 72), Dexa-BEAM (dexamethasone 3 × 8 mg/d days 1-10, carmustine 60 mg/m2/d day 2, melphalan 30 mg/m2/d day 2, cytarabine 2 × 100 mg/m2/d days 3-6, etoposide 75 mg/m2/d days 3-6, n = 2), CHOP (cyclophosphamide 750 mg/m2/d day 1, doxorubicin 50 mg/m2/d day 1, vincristine 1.4 mg/m2/d day 1, prednisone 100 mg/d days 1-5, n = 3), rituximab-CHOP (rituximab 375 mg/m2/d day 0, CHOP, n = 3), rituximab-CHOEP (rituximab 375 mg/m2/d day 0, CHOP plus etoposide 100 mg/m2/d days 1-3, n = 1), HAM (cytarabine 3,000 mg/m2 twice a day days 1-2, mitoxantrone 10 mg/m2/d days 2-3, n = 2), rituximab-HAM (rituximab 375 mg/m2/d, cytarabine 3,000 mg/m2 twice a day days 1-2, mitoxantrone 10 mg/m2/d days 23, n = 1), rituximab-Dexa-BEAM (rituximab 375 mg/m2/d day 0, Dexa-BEAM, n = 1), rituximab-docetaxel-cyclophosphamide (rituximab 375 mg/m2/d day 1, docetaxel 75 mg/m2/d day 2, cyclophosphamide 700 mg/m2/d days 2-4, n = 1), DHAP (dexamethasone 40 mg/d days 1-4, cisplatin 100 mg/m2/d day 1, cytarabine 2 × 2,000 mg/m2/d day 2, n = 4), FC (fludarabine 25 mg/m2/d days 1-4, n = 3, cyclophosphamide 750 mg/m2/d day 1), TCED (thalidomide 400 mg/d orally, etoposide 40 mg/m2/d days 1-4, cyclophosphamide 400 mg/m2/d days 1-4, dexamethasone 40 mg/d orally days 1-4, n = 9), CAD (cyclophosphamide 1,000 mg/m2/d day 1, doxorubicin 15 mg/m2/d days 1-4, dexamethasone 40 mg/d orally days 1-4, n = 3), MAMAC (cytarabine 2 × 1,000 mg/m2/d days 1-5, 4-[9-acridinylamino] methanesulphon-m-anisidide 100 mg/m2/d days 1-5, n = 1), vindesine (3 mg/m2/d day 1, n = 1),
G-CSF Dosages The patients received G-CSF starting 1 to 5 days after completion of CT according to the individual treatment protocol in dosages of 300-960 µg/d s.c. until the end of the collection period. CD34+ Cell Count Monitoring CD34+ PBSCs were monitored daily as soon as the WBC recovered (>1 × 109/l PB). Apheresis was scheduled to start when there were ≥20 × 106 CD34+ cells/l PB. If this target was not reached, other parameters, like increasing WBC or platelet reconstitution, were used to decide on leukapheresis trial. The minimal collection target was 2.0 × 106 CD34+ cells/kg bw. Our aim was to process three times the patient’s blood volume daily through an indwelling central or peripheral venous catheter using a cell separator (Spectra; COBE Laboratories; Heimstetten, Germany). Each leukapheresis product was cryopreserved in nitrogen until the day of transplantation. Immunofluorescence Staining and Flow Cytometry The absolute number of CD34+ cells was evaluated by flow cytometry using a FACScan analyzer (Becton Dickinson; Heidelberg, Germany; http://www.bd.com) and the appropriate isotype-matched, negative control, as has been described previously [8, 9]. Statistical Analyses The results are presented as median values, ranges, and correlation coefficients, where applicable. The relationships between different hematological parameters of the PB and leukapheresis products were analyzed by correlational statistics. Pearson’s sample correlation coefficient and the corresponding p value for the null hypothesis of no correlation were calculated. RESULTS In this retrospective analysis of patients who underwent stem cell apheresis and later received autologous PBSC transplantation in our institution, we determined the optimal time point for PBSC harvest. We used the maximum CD34+ cell concentration in the PB (peak [p]CD34+ cell count/l PB) as a surrogate marker for the mobilization potential. The patients mobilized a median of 111 × 106 CD34+ cells/l PB. As expected, the range was considerable, with a 260-fold variability among patients (7-1,767 × 106/l). A regression analysis revealed a correlation between the pCD34+ cell count and the CD34+ cell harvest obtained
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Figure 1. Correlation between the pCD34+ cell count (× 106/l) in the PB (x axis) and the number of CD34+ cells (× 106/kg bw) in the leukapheresis product (LP) (y axis). The correlation coefficient was 0.75 (n = 113, p = 0.0001). Both axes are plotted on a log scale.
(r = 0.75, p = 0.0001) (Fig. 1). In our study, the WBC was found to have no predictive value for the pCD34+ cell count in PB (n = 113, r = 0.42). The patients reached a pCD34+ cell count after a median of 14 days (range 6-32) after the start of mobilization chemotherapy. In 97% of all patients (109/113), apheresis was started on or after day 11 after initiation of mobilization CT. A subgroup analysis was performed to identify variables influencing mobilization kinetics. Diagnosis There was no significant difference in the PBSC mobilization kinetics between patients with multiple myeloma (n = 76) and others (n = 37) (Table 1).
Amount of Previous CT/RT As previously shown, the numbers of mobilized PBSCs were lower in severely pretreated patients (CT and RT) [10, 11]. This was observed when comparing patients who had received 1-6 premobilization cycles of CT with patients with more than six premobilization cycles (p < 0.000001). Similar results were observed in patients who had undergone prior RT compared with patients who had not received prior RT (p = 0.02). Interestingly, there was no significant difference in total CD34+ cell yield when comparing the group of patients with 0-3 previous CT cycles with the group with 46 cycles (p = 0.28). There was a trend that patients with higher numbers of CT regimens premobilization took longer to reach the pCD34+ cell concentration (Table 2) [12]. There were no differences in mobilization kinetics associated with RT. Patients (n = 32) who had undergone RT before mobilization reached a peak at a median of 14 days (range: 6-32) as did patients who had not received RT before mobilization (n = 81, range: 8-32). However, a higher proportion of preirradiated patients mobilized late (>day 20) when compared with nonirradiated patients (Table 1). This trend was not statistically significant. Mobilization Chemotherapy The effects of the type of CT on mobilization kinetics were studied. Sixty-six patients with MM were mobilized with high-dose cyclophosphamide CT, nine MM patients were mobilized with TCED, six patients with other diagnoses were mobilized with cyclophosphamide, and 32 patients with other diagnoses were mobilized with different mobilization regimens. There was no significant difference in the CD34+
Table 1. Mobilization kinetics CD34+ cell peak n of patients
Day 20
Diagnosis Multiple myeloma
76
3%
63%
30%
4%
Others
37
0%
68%
24%
8%
6
26
4%
58%
27%
12%
No
81
1%
67%
30%
2%
Yes
32
3%
59%
25%
13%
Prior chemotherapy (cycles)
Prior radiotherapy
The timing of the CD34+ cell peak was independent of the type of underlying malignancy and independent of prior RT or CT in previously untreated or mild to moderately pretreated patients. A subgroup analysis revealed that, among heavily pretreated patients (>6 cycles of prior CT or prior RT ), a higher proportion mobilized late (pCD34+ cell count later than day 20 in 12% and 13%, respectively, versus 2%-5% in the other groups, not significant).
Seggewiss, Buss, Herrmann et al.
571
Table 2. Influence of prior therapy on CD34+ cell mobilization A. Mobilization potential in chemotherapeutically pretreated patients n of patients
pCD34+ count (×× 106/l)
Days to pCD34+
Prior chemotherapy (cycles)
Median
Range
Median
Range
14
8-23*
151
27-1,767
4-6
14
10-21*
149
16-1,270
>6
15
6-32*
35
7-422
43
6 prior chemotherapy cycles), whereas there was no significant difference in the numbers of mobilized progenitor cells between patients who received 0-3 cycles of previous chemotherapy and patients who received 4-6 cycles of chemotherapy, p = 0.28. *one patient harvested day 6. B. Mobilization potential in irradiated/not irradiated patients n of patients
pCD34+ count (×× 106/l)
Days to pCD34+
Prior radiotherapy
Median
Range
Median
81
no
14
8-32*
130
32
yes
14
6-32*
86
Range 7-1,767 10-794
The numbers of mobilized CD34+ cells were significantly lower in patients who received prior radiotherapy compared with patients who did not receive prior radiotherapy, p = 0.02. *one patient harvested day 6.
mobilization kinetics among the 18 different mobilization CT regimens concerning the day of the pCD34+ cell count. The height of the pCD34+ cell count in PB was significantly greater in the cyclophosphamide group compared with the TCED-mobilized group. This might have been due to the fact that the patients mobilized with TCED were more severely pretreated, as TCED is a rescue chemotherapeutic scheme [13]. Furthermore, thalidomide has been reported to reduce stem cell yield by some authors [14], although these results could not be confirmed by our group [15]. The patients mobilized with cyclophosphamide had received a median of one previous CT treatment (range: 1-7), and the patients mobilized with TCED had a median of four previous CT treatments (range: 2-5). Interestingly, the kinetics of the peak mobilization were not different between these groups. G-CSF Dosages There was no difference in the peak day (median 14) between patients who received 300-480 µg/d G-CSF (once daily, range: 6-33 days) and those who received 600-960 µg/d G-CSF (twice daily, range: 8-32 days). The extent of the pCD34+ cells/l PB was higher in the group that received G-CSF 600-960 µg/d (n = 58, median pCD34+ cell count 175 × 106 cells/l, range 10.7-1,767 × 106 cells/l) than in the group that received only 300-480 µg/d G-CSF (n = 55, median pCD34+ cell count 92 × 106/l, range 7-794 × 106/l, p = 0.008) (Table 3A). However, when G-CSF-dosage was
adjusted for body weight, there was no significant difference in the pCD34+ cell count height (p = 0.34) (Table 3B). Patients who received ≤5 µg G-CSF/kg bw (n = 26) had a median pCD34+ cell count of 99 × 106 cells/l PB (range: 7-794 × 106), and patients who received >5 µg G-CSF/kg bw (n = 87) had a median pCD34+ cell count of 113 × 106/l PB (range: 11-1,767 × 106). Apheresis in Patients with a pCD34+ Cell Count ≤20 × 106/l PB Most apheresis centers measure the CD34+ cells/l PB and start the apheresis as soon as the CD34+ cell count exceeds 20 × 106/l or 25 × 106/l in the PB, because a pCD34+ count of >20 × 106/l PB has been shown to be a good predictor for sufficient apheresis [16]. In our group of 113 patients who harvested sufficient PBSCs, 10% (11/113) had less than 20 × 106 CD34+ cells/l PB and still were able to reach the collection target. Parameters to start leukapheresis in this patient group were rising WBC and concomitant thrombocyte reconstitution. If there were fewer than 2.0 × 105 CD34+ cells/kg bw in the first leukapheresis, we discontinued the collection trial. Patient characteristics for the poor mobilizers are shown in Table 4. There was no significant difference in the starting day of apheresis among all patients. The median for starting apheresis was the pCD34+ cell count day (day 14, range: days 5-28, p = 0.61). While the pCD34+ value occurred 2 days later in the poor mobilizer group than in the whole patient population, the range was also considerable
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Table 3. Influence of G-CSF dosage on the pCD34+ cell count A. Daily G-CSF dosage versus pCD34+ cells/l PB n of patients
pCD34+ count (×× 106/l)
Days to pCD34+
G-CSF dosage (µg/d)
Median
Range
Median
Range
55
300-480
14
6-33
92
7-794
58
600-960
14
8-32
174
11-1,767
No difference in the peak day (median 14) between the patients who received 300-480 µg/d G-CSF and those who received 600-960 µg/d was observed. The difference in the height of the CD34+ cell peak was statistically significant, p = 0.008. B. G-CSF dosage/kg bw versus pCD34+ cells/l PB n of patients
G-CSF dosage (µg/kg bw)
pCD34+ count (×× 106/l) Median
Range
26
5
113
11-1,767
For the body-weight-adapted G-CSF dosage, the difference in the height of the pCD34+ cell count was not statistically significant, p = 0.34.
(days 6-32), confirming that the height of the peak and the time point are independently regulated. DISCUSSION The speed of engraftment after myeloablative therapy is predicted by the number of CD34+ cells transplanted [17]. The apheresis procedures should be scheduled to achieve the desired target dose of CD34+ cells in a cost-effective and efficient manner. In our series of 113 patients, we found that 97% of all patients started collecting PBSCs after day 11, counted from the start of mobilization CT. This was independent of the diagnosis and the mobilization therapy as
well as the amount of previous CT or RT (Table 2A and 2B). We used 18 different mobilization CT regimens and did not find a significant difference in the day of reaching the pCD34+ cell count. This was shown previously for highdose cyclophosphamide versus DHAP in NHL patients [18]. In our retrospective study, we were unable to find a correlation between the pWBC/l and the pCD34+ cells/l PB, so the pWBC/l should not be used as a parameter to decide when apheresis should be started [17]. In contrast, the number of CD34+ cells in the PB was found to be a good predictor for the timing of apheresis in our heterogeneous population of patients aged 19-69 years with different
Table 4. Characteristics of poor mobilizers* n of patients and diagnosis
11
multiple myeloma
Sex
4 female
7 male
Age, median (range)
55 years
(40-61 years)
9
(4-20)
Number of previous CT cycles, median (range) Previous radiotherapy (n of patients) Mobilization regimen
6/11 7 TCED 4 CY
G-CSF dosage (µg/kg bw), median (range)
5.77
(2.8-12.31)
pCD34+ cell count (× 106/l), median (range)
16
(7-20.9)
Days to peak, median (range)
16
(6-32)
Number of LPs, median (range)
4
(1-8)
3.5
(1.0-7.9)
+
6
CD34 cell harvest (× 10 /kg bw), median (range)
*Poor mobilizers were patients with pCD34+ cell counts ≤20 × 106/l. Ten percent of all patients had CD34+ cell counts ≤20 × 106/l and still reached *the collection target. Abbreviations: CY = cyclophosphamide; LP = leukapheresis product.
Seggewiss, Buss, Herrmann et al. diagnoses. This finding has also been reported previously [19-21]. Sixty-seven percent of the patients at our center suffered from MM. There was no significant difference in the start of apheresis between the patients with MM and the others. We are unable to say whether it would make a difference when compared with stem cell diseases, like AML, which are treated with autologous PBSC transplantation [22], due to the fact that, in our study, there was only one AML patient. We observed a trend that patients who received more than six cycles of CT premobilization reached their pCD34+ cell count later and showed a lower maximal height of pCD34+ cells/l PB (e.g., 5% of all patients with fewer than four CT treatments reached the pCD34+ cell count after day 20 versus 12% of all patients with more than six CT treatments) (Table 1). This finding is in agreement with previous studies supporting that PBSC collection should be performed early in the course of disease to avoid CTinduced stem cell damage [12, 13, 23]. Based on our data, it would appear optimal, for our patient collective, to start measuring CD34+ cells in PB on day 11 after the start of mobilization CT and begin with leukapheresis as soon as CD34+ cell numbers >20 × 106/l are detected in the PB, as has been shown before. Our data argue for CD34+ cell measurement from day 11 and continuation until completion of PBSC harvest as the most promising and economical strategy for successful PBSC collection. This would be more economical and cost effective than starting leukapheresis, for example, on day 10 irrespective of WBC or blood CD34+ cell count, and to go on with leukapheresis for 6 days [24]. In such a schedule, a cumulative percentage of 77% of all patients with a minimum target collection of 2 × 106 CD34+ cells/kg bw was reported. Given the wide range of peak mobilization time points, starting leukapheresis without first measuring CD34+ cells in the PB would result in a greater number of expensive collection trials in patients. Perez-Simon et al. [25] showed, in a retrospective analysis of 263 PB samples and their corresponding leukapheresis component, that a presence of more than 5 × 106 CD34+
573
cells/l PB ensured a sufficient PBSC harvest in 95% of patients and avoided an unsuccessful harvest in 81% of cases. Chapple et al. [26] prospectively analyzed, in 59 patients with various malignancies, the correlation between CD34+ cells/l PB and PBSC count and also found a CD34+ cell count of at least 5 × 106/l PB sufficient to successfully collect PBSCs. A low baseline number of CD34+ cells/l PB does not permit a priori the exclusion of patients from apheresis, since 10% of all patients in our series had less than 20 × 106 CD34+ cells/l PB and still had sufficient CD34+ cells collected. Parameters to start apheresis in this group were rising WBC and platelet reconstitution. In our institution, 96% of all patients had a sufficient autograft collected, containing more than 2 × 106 CD34+ cells/kg bw. Only patients with a pCD34+ cell count of less than 1 × 106 cells/l regularly failed the apheresis target (data not shown). Therefore, we propose to do an evaluation leukapheresis in those cases if the pCD34+ cell count is at least >1 × 106/l PB after day 11 after initiation of CT and if the WBC is rising and platelet reconstitution to values >100 × 109/l has occurred. CONCLUSION This is one of the largest series of patients reported with a focus on PBSC mobilization kinetics. The data should allow better planning of PBSC collection in an outpatient setting. We suggest to start measuring CD34+ cells in PB on day 11 after the start of mobilization CT and begin with leukapheresis as soon as a CD34+ cell count >20 × 106/l is detected in the PB. In the patient group with lower CD34+ cell counts but rising WBC, thrombocyte reconstitution, and CD34+ cell counts >1 × 106/l, we recommend an evaluation leukapheresis. ACKNOWLEDGMENTS We thank the study center of our hospital, especially Elke Brants and Annemarie Geueke, for help in collecting clinical data. We are obliged to the technical staff in the transplantation laboratory for assistance in data analysis. We thank Thomas E. Prisinzano for critical reading of the manuscript.
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