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Keywords:

  • mobilization;
  • CD34+ cells ;
  • G-CSF;
  • malignant lymphoma;
  • peripheral stem cell support

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References

We compared retrospectively the efficacy of granulocyte colony stimulating factor (G-CSF) alone with chemotherapy plus G-CSF in mobilizing CD34-positive cells in patients with malignant lymphoma. 35 patients underwent peripheral blood stem cell (PBSC) collection following mobilization either with 24 μg/kg G-CSF for 4 consecutive days (n = 18) or Dexa-BEAM chemotherapy plus 5 μg/kg G-CSF (n = 17). High-dose G-CSF was well tolerated with only slight bone pain and/or myalgia. The Dexa-BEAM therapy required hospitalization with a median duration of 21 d. The median number of apheresis procedures in both groups was two (range two to four), resulting in a median of 5.3 and 5.1 × 106 CD34+ cells/kg. No patients in the G-CSF group, but one in the Dexa-BEAM group, failed to reach the target of collecting >2.0 × 106 CD34+ cells/kg. The number of CFU-GM (10.4 v 6.0 × 105/kg) and of BFU-E (10.6 v 4.5 × 105/kg; P = 0.04) was higher in the G-CSF group than in the Dexa-BEAM group. A subset analysis of CD34+ cells was performed in 16 patients showing a higher mean of Thy-1 (CD90w) coexpression in the G-CSF than in the Dexa-BEAM group (4.8 v 1.8%, P = 0.12). Additionally the percentage of CD34+/CD38 cells was higher in the G-CSF group (10.6% v 8.8%). However, these differences were not stastistically significant. The median time to leucocyte and platelet engraftment after high-dose chemotherapy was slightly shorter in the G-CSF than in the Dexa-BEAM group (9 v 10 and 12 v 13.5 d, respectively). These results demonstrate that high-dose G-CSF is as effective as Dexa-BEAM plus G-CSF in mobilizing peripheral blood stem cells and produces prompt engraftment. The major advantages of G-CSF mobilization were the safe outpatient self-application and the fixed-day apheresis.

High-dose chemo-radiotherapy followed by autologous blood stem cell support is increasingly used in the treatment of patients with high-risk or relapsed non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) ( Horning et al, 1994 ; Haioun et al, 1997 ; Kessinger et al, 1991 ; Haas et al, 1994 ). A randomized trial confirmed the superiority of high-dose chemotherapy followed by autologous bone marrow transplantion over standard salvage therapy for relapsing chemosensitive NHL ( Philip et al, 1995 ). Peripheral blood stem cell (PBSC) transplantion is now preferred to autologous bone marrow transplantation because of its more rapid engraftment of both neutrophils and platelets ( To et al, 1992 ; Schmitz et al, 1996 ). Mobilization of PBSC can be achieved with chemotherapy ( Schwartzberg et al, 1992 ) or cytokine alone ( Sheridan et al, 1992 ; Chao et al, 1993 ; Bensinger et al, 1994 ; Nademanee et al, 1994 ; Zeller et al, 1996 ) or with combination of both ( Gianni et al, 1989 ; Pettengell et al, 1993 ; Dreger et al, 1993 ; Jones et al, 1994 ; Haas et al, 1994 ; McQuaker et al, 1997 ). The dose of PBSC infused, as measured by CD34+ cell count, has been found to be an important predictor of engraftment regardless of disease or technique of mobilization ( Bensinger et al, 1995 ; Weaver et al, 1995 ). Therefore the optimal technique of mobilization still needs to be determined. The addition of cytokine to chemotherapy enables more PBSCs to be collected with fewer apheresis procedures than chemotherapy alone ( Schwartzberg et al, 1992 ). Dexa-BEAM has been reported to be an effective regimen for mobilizing PBSC in lymphoma patients ( Dreger et al, 1993 ). However, inadequate PBSCs collection was observed after chemotherapy plus G-CSF mobilization in some heavily pretreated patients ( Haas et al, 1994 ; Dreger et al, 1995 ). Additionally, these lymphoma patients had several problems with chemotherapy including neutropenic fever and non-haematological toxicity that could require hospitalization ( Dreger et al, 1995 ). A sufficient yield of PBSCs in lymphoma patients can be achieved with G-CSF (10 μg/kg) alone ( Nademanee et al, 1994 ). In a small study of seven patients with breast cancer, chemotherapy plus G-CSF resulted in a higher yield of PBSCs than low-dose G-CSF (300 μg) alone ( Möhle et al, 1994 ). We recently reported a dose–response effect on CD34+ cell mobilization with 10 and 24 μg/kg G-CSF in lymphoma patients ( Zeller et al, 1996 ). The current study was undertaken to compare the efficacy of high-dose G-CSF (24 μg/kg) versus Dexa-BEAM chemotherapy plus G-CSF (5 μg/kg) in mobilizing CD34+ cells, CD34+ cell subset and progenitor cells as well as on the haemopoietic engraftment in lymphoma patients.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References

Patients

In the present retrospective study 35 patients with high-risk or relapsed malignant lymphoma were referred between 1995 and 1997 for peripheral blood stem cell collection before high-dose chemo-radiotherapy. 12 patients had HD and 23 had NHL (14 high-grade, nine low-grade). NHL was classified according the Kiel and REAL classifications ( Lennert & Feller, 1990; Harris et al, 1994 ). All patients provided written informed consent for Dexa-BEAM chemotherapy, for administration of G-CSF, collection of peripheral blood stem cells and for high-dose chemotherapy. There was no randomization between the mobilization procedures. Most of the Dexa-BEAM patients were referred for apheresis by other hospitals or were treated on lymphoma protocols. The median number of previous cycles of chemotherapy was 6.5 (range three to 24). The mobilization procedure was performed in 18 patients with high-dose G-CSF (24 μg/kg) alone, and 17 patients received Dexa-BEAM chemotherapy with G-CSF (5 μg/kg). Both groups were well balanced in terms of age, previous chemo- and radiotherapy and histology. The patient characteristics are listed in Table I. Dexa-BEAM chemotherapy required hospital admittance and included Dexamethasone 3 × 8 mg days 1–8, BCNU 60 mg/m2 day 2, etoposide 150 mg/m2 days 4–7, cytarabine 100 mg/m2 q12 h days 4–7, and melphalan 20 mg/m2 day 3. G-CSF (5 μg/kg, s.c.) was applied from day 8 until the last day of PBSC. Generally apheresis was started after the white blood count (WBC) exceeded 10 × 109/l as recommended ( Dreger et al, 1993 ).

Table 1. Table I. Characteristics of 35 lymphoma patients undergoing PBSC mobilizing therapy.Thumbnail image of

High-dose G-CSF (filgrastim; Amgen, Munich, Germany) was applied subcutaneously at a dose of 12 μg/kg twice daily with a time interval of 12 h. Apheresis was started on day 5, usually 2–3 h after the last injection. G-CSF application was continued until completion of leukapheresis ( Zeller et al, 1996 ). The minimum target of collection was >2.0 × 106 CD34+ cells/kg.

PBPC collection and cryopreservation

The collection of PBPC was performed with a Cobe Spectra using a 250 ml volume collection chamber. A total of 8–10 litres of blood per apheresis was processed at a flow rate of 50–70 ml/min; a mean volume of 250 ml was collected. This cell suspension was concentrated to a final volume of 50 ml and was mixed with 50 ml of minimal essential medium (MEM) containing 20% dimethylsulphoxide. The final 100 ml harvest product was transferred into freezer bags and frozen to −100°C with a computer-controlled cryopreservation device. The frozen cells were transferred into liquid nitrogen and stored at −196°C as described previously ( Hassan et al, 1996b ).

Progenitor cell assays

Unseparated MNC (1 × 105/ml) were grown in a 1.25% methylcellulose solution containing 10% lymphocyte-conditioned medium, 10% human plasma, 20% fetal calf serum, 9% Iscoves medium, 2-mercaptoethanol, and 3 U/ml erythropoietin. After a 14 d period of incubation in a humidified atmosphere with 5% CO2 and at 37°C, colony forming units granulocyte-macrophage (CFU-GM) and BFU-E were counted using an inverted microscope as described ( Hassan et al, 1996b ).

Immunofluorescence staining and flow cytometry

For determination of CD34-positive cells, 1 × 106 mononuclear cells (MNC), separated by Ficoll-Hypaque density gradient centrifugation, were incubated for 30 min at 4°C in darkness with phycoerythrin (PE)-conjugated monoclonal antibody anti-CD34 (HPCA-2, Becton Dickinson, Heidelberg, Germany). Analysis was performed on a FACScan flow cytometer (Becton Dickinson) with LYSIS II software (Becton Dickinson) according to the method published by Siena et al (1991 ). A minimum of 10 000 events were counted. To calculate the total CD34+ cells, the number of MNC per leukapheresis product was multiplied by the percentage of CD34+ cells. On thawed samples, subset analysis of CD34+ cells was performed on cells acquired in a CD34 fluorescence/SCC gate. The following antibodies were used: (PE)-conjugated monoclonal antibody anti-CD34 (HPCA-2, Becton Dickinson, Heidelberg, Germany), and fluorescein (FITC)-conjugated monoclonal antibodies anti-CD38 (DAKO, Hamburg, Germany), anti-CDw90 (Immunotech, Hamburg, Germany). Isotype-identical antibodies were used as controls: IgG1, IgG2a (FITC/PE-conjugated, Becton Dickinson, Heidelberg, Germany). A minimum of 100 events in the CD34+ cell gate were required.

High-dose chemotherapy

At time of analysis 10 patients from the Dexa-BEAM and 18 patients from the G-CSF group had been transplanted. High-dose chemotherapy consisted of total-body irradiation (TBI) and cyclophosphamide (Cy) (n = 2), TBI, Cy and etoposide (n = 5), BCNU, etoposide, melphalan and cytarabinoside (BEAM) (n = 15), busulphan, Cy, etoposide (n = 5) or busulphan, thiotepa and etoposide (n = 1) ( Table I). All protocols were approved by the local ethics committee.

Statistics

Statistic analysis was performed using WinSTAT software (Kalmia Co. Inc., Cambridge, Mass.). For comparison of the two mobilizing regimens the independent t-test was used. The correlation analysis was calculated by Pearson test. A P-value of < 0.05 was considered significant.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References

Toxicity

G-CSF administration was well tolerated with only slight bone pain in 61% of the patients. The Dexa-BEAM therapy required hospitalization for a median of 21 d (range 18–24). Most of the patients experienced fever during neutropenia, with a median duration of 3 d (range 0–5). In the Dexa-BEAM group the median days of i.v. antibiotic therapy was 6 d (range 0–7) and the median number of platelet transfusions was one (range one to two) ( Table II).

Table 2. Table II. Toxicities and supportive therapy.Thumbnail image of

PBSC collection

Stem cell collection was started after a median of 18 d (range 13–21) of Dexa-BEAM chemotherapy. The median number of WBC at time of first apheresis was 13.5 × 109/l (range 3.4–42 × 109/l). In the G-CSF group apheresis was started on day 5 of G-CSF application. In both groups a median of two apheresis procedures (range one to four) were performed, resulting in an overall number of 5.1 (range 0.3–24.8) and 5.3 (range 2.1–19) × 106 CD34+ cells/kg. In the first apheresis a median of 3.9 × 106 (range 0.2–24.8) and of 3.2 × 106 (range 1.0–13.1) CD34+ cells/kg could be harvested in the Dexa-BEAM and the G-CSF group, respectively. None in the G-CSF group, but one patient in the Dexa-BEAM group, failed to achieve the target collection of >2.0 × 106 CD34+ cells/kg. The overall number of CFU-GM was higher in the G-CSF than in the Dexa-BEAM group: 10.4 × 105 (range 1.6–128) versus 6.0 × 105 (range 0.8–90) but was not statistically significant. Significantly higher numbers of BFU-E were obtained in the G-CSF group: 10.6 × 105 (range 2.6–43) versus 4.5 × 105 (range 1.2–50), P = 0.04 ( Table III, Fig 1 ).

Table 3. Table III. Progenitor cell dose and colony forming units.Thumbnail image of
image

Figure 1. Fig 1. CD34+ cell yield and cloning efficiency after mobilization with G-CSF alone or Dexa-BEAM plus G-CSF. ns: not significant.

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CD34+ cell subsets

Sixteen samples were evaluated for CD34 subset analysis (G-CSF group n = 7; Dexa-BEAM group n = 9). The mean percentage of CD34+/Thy-1 (CD90w)+ cells and of CD34+/CD38 cells were higher in the G-CSF- than in the Dexa-BEAM group (4.86% v 1.8% and 10.6% v 8.8%). However, the differences did not reach statistical significance.

Engraftment

Eighteen patients from the G-CSF group and 11 patients of the Dexa-BEAM group underwent high-dose chemo-radiotherapy. Reasons for not completing high-dose therapy in the Dexa-BEAM group were: early progress (n = 2), <1.0 × 106 CD34+ cells/kg harvested (n = 1) and too early for evaluation (n = 3). A prompt engraftment was seen in all patients: a slightly faster engaftment with leucocyte count >1.0 × 109/l was observed in the G-CSF group: 9 d (range 8–12) v 10 d (range 7–13). Additionally, a platelet count of >20 × 109/l was reached by the G-CSF group after a median of 12 d (range 9–150) and by the Dexa-BEAM group after a median of 13.5 d (range 11–26). These differences, however, did not reach statistical significance ( Table IV).

Table 4. Table IV. Engraftment with G-CSF or Dexa-BEAM + G-CSF mobilized progenitor cells. Thumbnail image of

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References

The rapid haemopoietic reconstitution after high-dose chemo-radiotherapy in patients with malignant lymphoma is due to the large number of progenitor cells collected by various stem cell mobilization regimens which may consist of chemotherapy, haemopoietic growth factors or both. The optimal mobilization regimen, however, in terms of safety, progenitor cell dose, engraftment and tumour cell contamination, remains to be determined. The addition of growth factors to chemotherapy has provided a better mobilization than chemotherapy alone and may ameliorate haematological toxicity ( Pettengell et al, 1993 ; Schwartzberg et al, 1992 ). Few studies have compared the efficacy of growth factors with different chemotherapy protocols. In patients with multiple myeloma, high-dose cyclophosphamide (7 g/m2) was more effective in mobilizing PBSC with less tumour cell contamination than intermediate dose (4 g/m2) ( Goldschmidt et al, 1996 ). The addition of etoposide improved mobilization with cyclophosphamide in myeloma patients, resulting in 92% of patients reaching the target of >5.0 × 106 CD34+ cells/kg in comparison to only 43% of the patients who received only cyclophosphamide ( Demirer et al, 1996 ). In lymphoma patients, combination chemotherapy consisting of etoposide, ifosfamide and epirubicin plus G-CSF resulted in a significantly higher amount of CD34+ cells than mobilization with cyclophosphamide (3–4 g/m2) plus G-CSF (8.62 × 106v 3.59 × 106) ( McQuaker et al, 1997 ).

G-CSF alone mobilizes sufficient progenitor cells in lymphoma patients to allow positive selection of CD34+ cells ( Mahéet al, 1996 ; Hassan et al, 1996a ). Recently, our group has shown a fourfold increase in CD34+ cell harvest by inreasing the G-CSF dose from 10 to 24 μg/kg in patients with malignant lymphoma and testicular cancer ( Zeller et al, 1996 ).

The present study has shown that in lymphoma patients high-dose G-CSF (24 μg/kg) is at least as effective as the commonly used Dexa-BEAM chemotherapy plus G-CSF (5 μg/kg). No patient in the G-CSF group but one in the Dexa-BEAM group failed to achieve the target collection of >2.0 × 106 CD34+ cells/kg. We found no difference in the CD34+ cell yield, but a higher number of CFU-GM (10.4 v 6.0 × 105/kg; n.s.) and of BFU-E (10.6 v 4.5 × 105/kg; P = 0.04) in the G-CSF group. Only one small study has compared chemotherapy plus G-CSF with G-CSF alone in mobilizing PBSCs in seven breast cancer patients. Mobilization with chemotherapy plus G-CSF resulted in a higher amount of CD34+ cells and of CFU-GM than with low-dose G-CSF alone ( Möhle et al, 1994 ). These differences might be explained by the different dose of G-CSF used in both studies. In our study 2 × 12 μg/kg G-CSF was used, whereas Möhle et al (1994 ) used only 300 μg G-CSF. The subset analysis of CD34+ cells in flow cytometry, however, showed similiar results, with higher of CD38 and lower Thy1 coexpression in the chemotherapy group, which might indicate more lineage commitment of the mobilized CD34+ cells ( Terstappen et al, 1991 ; Craig et al, 1993 ). The advantage of Dexa-BEAM plus G-CSF as mobilization regimen is that it can be carried out as an integrated part of the chemotherapy protocol. Furthermore, there might be an in-vivo purging effect of the graft, but tumour cell contamination has not been addressed in this study. In conclusion, stem cell mobilization G-CSF alone at an optimal dose was at least equal to Dexa-BEAM plus G-CSF in terms of CD34+ cell harvest, CFU-GM and BFU-E and ensures rapid engraftment. Thus, the advantages of mobilization with G-CSF alone are predictability of harvest time without chemotherapy-related toxicity and need of hospitalization.

References

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References
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