Successful Peripheral Blood Stem Cell Mobilization with Etoposide (VP- 16) in Patients with Relapsed Or Resistant Lymphoma Who Failed Cyclophosphamide Mobilization

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Bone Marrow Transplantation, (1999) 23, 1223–1228  1999 Stockton Press All rights reserved 0268–3369/99 $12.00 http://www.stockton-press.co.uk/bmt Successful peripheral blood stem cell mobilization with etoposide (VP- 16) in patients with relapsed or resistant lymphoma who failed cyclophosphamide mobilization

1 1 1 2 1 1 1 1 M Reiser , A Josting¨ , A Draube , MY Mapara , C Scheid , J Chemnitz , H Tesch , J Wolf , V Diehl1,DSohngen1 and A Engert1 ¨ ¨ 1First Department of Internal Medicine, University Hospital Koln, Koln; and 2Department of Hematology, Oncology, and ´ Tumorimmunology, University Center Charite, Berlin, Germany

Summary: are no standard regimens for inducing mobilization of peripheral blood stem cells (PBSC) based on randomized com- High-dose chemotherapy (HDCT) followed by autolog- parisons. In patients with malignant lymphomas, cyclopho- ous blood stem cell transplantation is considered the sphamide at different dose levels ranging from 1.5 to 7 g/m2 treatment of choice for patients with relapsed or resist- followed by granulocyte colony-stimulating factor (G-CSF) ant aggressive non-Hodgkin’s lymphoma (NHL) or at doses of 5 to 10 ␮g/kg/day is mainly used to mobilize Hodgkin’s disease (HD). However, several authors PBSC.1–3 Stem cells are harvested by leukapheresis to col- report failure of standard mobilization regimens in 29% lect at least 2.0 ϫ 106 CD34+ cells/kg. Various factors to 56% of these patients making the completion of influencing the stem cell yield have been identified, eg HDCT impossible and as a result, negatively influencing tumor type, stage of disease, pretreatment,4 interval long-term outcome. Thus, effective new regimens for between drug courses,5,6 prior radiotherapy, dose of G-CSF patients failing initial mobilization are needed. Here we and chemotherapy used for PBSC mobilization.7–10 Mobil- report the results of using etoposide as a mobilizing ization is more effective in patients at diagnosis as com- agent in 16 patients with primary resistant or relapsed pared to patients with resistant or relapsed disease.8 The malignant lymphoma who had failed prior mobilization diagnosis of malignant lymphoma and in particular Hodg- of peripheral blood stem cells (PBSC) with cyclophos- kin’s disease has been associated with a poor mobilization phamide (4 g/m2) followed by G-CSF. The use of etopo- efficacy.4 Thus, the use of currently available mobilization side 500 mg/m2 (days 1–4) + G-CSF resulted in the suc- protocols does not ensure adequate PBSC mobilization in cessful collection of adequate numbers of PBSC with a pretreated lymphoma patients. In this situation autologous median harvest of 3.6 × 106/kg (range 2.2–12.6) CD34+ bone marrow cells, alone or mixed with PBSC, may be cells in all 16 patients. In 7/16 (44%) patients, the target used to allow treatment with HDCT. Since the results of yield of at least 2.0 × 106 CD34+ cells was harvested by autologous bone marrow transplantation (ABMT) are pro- a single apheresis and the maximum number of separ- ven inferior to PBSCT in terms of time to engraftment and ations for all patients was two. No excessive toxicities infectious complications, the use of PBSC is preferred by appeared, allowing all patients to proceed to myeloabl- most centers.11,12 To investigate a different mobilization ative chemotherapy. In addition, median peak values of strategy, we used etoposide in patients with relapsed or circulating CD34+ cells were significantly higher after resistant lymphoma. Here, we report on 16 patients with etoposide as compared to cyclophosphamide (49.2/␮l vs multiple risk factors for low stem cell yield who failed a 4.7/␮l; P = 0.0004). These results indicate that etoposide first cycle of high-dose cyclophosphamide. After a second + G-CSF is a highly effective mobilization regimen in mobilization attempt with high-dose etoposide all patients patients who have failed cyclophosphamide mobiliz- were successfully mobilized and proceeded to high-dose ation. chemotherapy without autologous bone marrow harvest. Keywords: stem cell mobilization; CD34+ cells; etoposide; cyclophosphamide; mobilization failure; stem cell transplantation Patients and methods

Patient characteristics and treatment protocol High-dose chemotherapy (HDCT) followed by peripheral Between August 1997 and October 1998, etoposide mobil- blood stem cell transplantation (PBSCT) is being increas- ization was evaluated in all consecutive patients who had ingly used in patients with malignancies. However, there failed an initial cyclophosphamide mobilization. The patient characteristics are summarized in Table 1. Eight Correspondence: Dr M Reiser, First Dept of Internal Medicine, University male and eight female patients with a median age of 40 ¨ ¨ Hospital Koln, Joseph-Stelzmann-Str 9, 50924 Koln, Germany years (range 22–68) entered this study. Histology was reas- Received 23 November 1998; accepted 19 January 1999 sessed by lymph node biopsy at relapse according to the Successful PBSC mobilization with etoposide M Reiser et al 1224 Table 1 Patient characteristics (n = 16) PBSC harvesting

Number of patients 16 Leukocyte count was monitored daily after mobilization chemotherapy and the percentage of CD34+ cells was Age (years) Ͼ ␮ Median 40.0 assessed when leukocytes were 1000/ l. Leukaphereses + Range 22–68 were performed when CD34 cell counts reached more than Sex 10 cells/␮l. The blood volume of each patient was routinely Male 8 processed three times by using the Cobe Spectra Female 8 (Lakewood, CO, USA) or the Fresenius AS 104 cell separ- Histology ator (St Wendel, Germany) according to the manufacturer’s Hodgkin’s lymphoma 8 recommendations to collect at least 2 ϫ 106 CD34+ Diffuse large B cell 4 + Follicular center 3 cells/kg. Leukapheresis was stopped on the day the CD34 Peripheral T cell 1 cell count declined and a single large volume apheresis ϫ 6 + Relapse status resulted in less than 0.4 10 CD34 cells/kg. Leukocyte Refractory 6 surface phenotype analysis using flow cytometry was per- Relapse 10 formed as previously reported.16 Mononuclear cells were Stage at relapse stained with fluorescein isothiocyanate (FITC)- and phyco- I1erythin (PE)-conjugated CD34 (anti-HPCA-2, Becton II 7 III 4 Dickinson, San Jose, CA, USA) monoclonal antibodies IV 4 with mouse IgG as a negative control and counterstaining Symptoms was performed with anti-CD45. More than 20 000 cells A14were analyzed with flow cytometry using a FACScan flow B2cytometer (Becton Dickinson) with Cellquest software. The frequency of colony-forming hematopoietic progenitor cells was evaluated as previously described.17 Patients were considered mobilization failures if the CD34+ cell count did not reach Ͼ10 cells/␮l or if stem cell harvest was below 2.0 ϫ 106/kg. REAL-classification. Eight patients with Hodgkin’s disease Statistical analyses were performed using the Wilcoxon and eight patients with non-Hodgkin’s lymphoma had matched-pairs signed-rank test (SPSS version 6.1.3, SPSS failed to respond to first-line chemotherapy or had relapsed Inc, Chicago, IL, USA). after achieving a complete response. Eleven patients received a new high-dose sequential protocol with two initial cycles of DHAP (cisplatin, cytarabine, Results dexamethasone)13 and five patients received the Dexa- BEAM protocol with two initial cycles of Dexa-BEAM Overall, 16 patients were treated with high-dose cyclophos- (dexamethasone, BCNU, melphalan, etoposide and phamide 4 g/m2 and failed to mobilize adequate numbers cytarabine).14,15 DHAP and Dexa-BEAM were repeated of peripheral blood stem cells. Individual risk factors influ- after 14 or 29 days, respectively. After achieving CR or encing stem-cell mobilization and mobilization outcome PR patients received high-dose cyclophosphamide (4 g/m2) including pretreatment and time interval between last followed by G-CSF (2 ϫ 5 ␮g/kg) in order to mobilize per- chemotherapy are summarized in Table 2. The median peak value of peripheral CD34+ cells was 4.7/␮l (range 0–15.2) ipheral blood stem cells. After DHAP all 11 patients were 2 2 after cyclophosphamide 4 g/m + G-CSF. Three of 16 consecutively treated with high-dose methotrexate (8 g/m ) + ␮ plus vincristine (1.4 mg/m2) and after hematological recon- patients reached more than 10 CD34 cells/ l but had inad- ϫ 6 stitution with high-dose etoposide 500 mg/m2 (days 1–4) aquate collection of stem cells (0.2, 0.2 and 1.01 10 CD34+ cells/kg, respectively). Overall, mobilization with as 8-h infusion plus G-CSF (2 ϫ 5 ␮g/kg). The five patients cyclophosphamide + G-CSF resulted in a median progeni- treated with the Dexa-BEAM regimen received high-dose + tor yield of 0.0 ϫ 106 CD34 cells/kg (range 0–1.0) and etoposide after mobilization failure with cyclophospham- 0.0 ϫ 104 CFU-GM/kg (range 0–20.9) in those 16 patients. ide. Six patients with Hodgkin’s disease and five patients Toxicity of cyclophosphamide was mainly hematological. with high-grade non-Hodgkin’s lymphoma entered the All patients experienced WHO grade IV leukocytopenia high-dose sequential protocol. Three patients with low- (leukocytes Ͻ1000/␮l) and thrombocytopenia (platelets grade NHL and two patients with HD at second relapse Ͻ25 000/␮l) with a median duration of 5.0 (range 3–8) and were treated according to the Dexa-BEAM protocol. Eight 5.0 (range 3–9) days, respectively. Patients received cyclo- of 16 patients had advanced disease (stage III and IV). phosphamide for mobilization at a median of 25 days Overall, patients were intensively pretreated with aggress- (range 19–147) after the last cycle of induction treatment. ive combination chemotherapy and a median of eight cycles The median time interval between cyclophosphamide and (range 1–11) of different regimens. 38% (6/16) of the etoposide mobilization was 39 days (range 25–65). In this patients had prior radiotherapy. Six patients had failed to respect, there was no difference for patients treated accord- achieve CR after initial first- or second-line treatment and ing to the high-dose sequential protocol and patients treated 10 patients were in their first remission. with the Dexa-BEAM regimen (median 40 days (range 25– Successful PBSC mobilization with etoposide M Reiser et al 1225 Table 2 Potential risk factors in 16 patients with failure to cyclophosphamide mobilization

Patient Diagnosis Relapse Prior chemotherapy Prior radiotherapy Time interval between No. status last chemotherapy and cyclophosphamide (days)

1HDPD8× BEACOPP, 2 × DHAP no 27 2 hg-NHL PD 6 × CHOP, 2 × DHAP yes 25 3 hg-NHL PD 6 × CHOP, 2 × DHAP no 22 4 HD relapse 2 × COPP/ABVD, 2 × DHAP yes 20 5 HD relapse 4 × COPP/ABVD, 2 × DHAP yes 22 6 hg-NHL relapse 6 × CHOP, 2 × DHAP no 25 7 HD relapse 2 × COPP/ABVD, 2 × DHAP yes 22 8 lg-NHL PD 5 × CHOP, 1 × DexaBeam no 50 9 HD relapse 3 × MOPP, 5 × BEACOPP, 2 × DexaBEAM no 147 10 HD PD 7 × BEACOPP, 2 × DexaBEAM no 54 11 lg-NHL relapse 8 × MCP, 2 × DexaBEAM no 65 12 lg-NHL relapse 6 × COP, 2 × DexaBEAM no 46 13 hg-NHL relapse 6 × CHOP, 2 × DHAP no 19 14 HD PD 4 × COPP/ABVD, 4 × BEACOPP no 21 15 hg-NHL relapse 6 × CHOEP, 4 × DIZE + BEAM yes 21 16 HD relapse 4 × COPP/ABVD yes 24

BEACOPP = bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbine, prednisone; DHAP = dexamethasone, cytarabine, platin; CHOP = cyclophosphamide, adriamycin, vincristine, prednisone; COPP/ABVD = cyclophosphamide, vincristine, procarbacine, prednisone, adriamycin, bleomycin, vinblastine, dacarbacine; DexaBEAM = dexamethasone, BCNU, etoposide, cytarabine, melphalan; COP = cyclophosphamide, vincristine, prednisone; MCP = mitoxantrone, chlorambucil; prednisone; DIZE = dexamethasone, ifosfamide, idarubicin, etoposide.

65) vs 39 days (range 32–61)). All 16 patients had successful stem cell mobilization following high-dose etoposide at 60 Etoposide 2 g/m2. Mobilization characteristics for all 16 patients are Cyclophosphamide

shown in Table 3. With a median of 2.0 (range 1–2) leu- l kaphereses, 3.6 ϫ 106 CD34+ cells/kg (range 2.2–12.6) and µ 40 24.2 ϫ 104 CFU/kg (range 1.1–52.6) were harvested after cells/ etoposide and G-CSF. In 7/16 (44%) patients the collection + ϫ 6 + of the target yield of at least 2.0 10 CD34 cells was 20 possible with a single apheresis, and the maximum number CD34 of leukaphereses for all 16 patients was two. The median peak values of circulating CD34+ cells were signiﬁcantly lower after cyclophosphamide compared with etoposide 0 9 10 11 12 13 14 15 16 17 18 19 20 21 22 (4.7/␮l (range 0–15.2) vs 49.2/␮l (range 16.3–122); P = 0.0004). Circulating CD34+ cells were signiﬁcantly higher Days after mobilization after etoposide with a mean difference of 46.2 cells/␮l Figure 1 Mean (Ϯ s.d.) of circulating CD34+ cells/␮l after the beginning (95% CI: 26.1–66.3). The mean values of circulating of infusion of etoposide 2 g/m2 and cyclophosphamide 4 g/m2 in 16 CD34+ cells for each day after mobilization are shown in patients failing initial cyclophosphamide mobilization. Mean difference: + ␮ Ͻ Figure 1. 46.2 CD34 cells/ l (95% CI: 26.1–66.3; P 0.001). The maximum increase of PBSC occurred between days 13–15, following cyclophosphamide and days 15–17 after 140 etoposide, therapy. After etoposide 15/24 leukaphereses Cyclophosphamide were performed between day 14 and 16 (Figure 2). In each 120 Etoposide

l 100 Table 3 Mobilization characteristics after cyclophosphamide and µ etoposide in 16 patients with cyclophosphamide failure 80 cells/ + 60 Cyclophosphamide Etoposide 2 + 2 + 4 g/m G-CSF 2 g/m G-CSF CD34 40 (n = 16) (n = 16) 20 Peak CD34+ cells/␮l median (range) 4.7 (0–15.2) 49.2 (16.3–122.0)a 0 12345678910111213141516 CD34+ cells (× 106/kg) 0.0 (0–1.0) 3.6 (2.2–12.6)a Patients CFU-GM (× 104/kg) 1.4 (0–20.9) 24.2 (1.1–52.6)b Figure 2 Leukapheresis starting date. Starting date is the number of days aWilcoxon matched-pairs signed-rank test, P = 0.0004. from the beginning of etoposide infusion to the first day of leukapheresis. bWilcoxon matched-pairs signed-rank test, P = 0.0007. 15/24 (63%) leukaphereses were performed between days 14 and 16. Successful PBSC mobilization with etoposide M Reiser et al 1226 7 14/16 received red blood cell transfusions (median 2.0; range 0–6). 6 Until October 1998, 13/16 patients received high-dose 5 chemotherapy. Median time of leukocytopenia (leukocytes Ͻ1000/␮l) was 10 days (8–11) and median time to last 4 platelet transfusion after the beginning of BEAM was 18 3 days (13–31). These data compare favourably to engraftment patterns described for conventional mobilized 2 PBSC. 1 Number of leukaphereses 0 Discussion 10 11 12 13 14 15 16 17 18 19 20 21 22 Days after beginning of etoposide administration The following findings emerge from this study: (1) high- 2 + dose etoposide (500 mg/m ; days 1–4) plus G-CSF is an Figure 3 Peak values of peripheral CD34 cells for each individual patient after cyclophosphamide 4 g/m2 and etoposide 2 g/m2 mobilization. effective method for mobilizing PBSC in patients who have In 16/16 patients peripheral CD34+ cell peak was higher after etoposide failed initial cyclophosphamide mobilization. (2) This regi- compared to cyclophosphamide. men is associated with moderate nonhematological toxicity even in heavily pretreated lymphoma patients. (3) Peak values of circulating CD34+ cells and number of collected individual patient, the maximum number of peripheral + stem cells were significantly higher after high-dose etopo- CD34 cells was higher after etoposide as compared to 2 + side compared with cyclophosphamide 4 g/m . (4) The use cyclophosphamide. Peak values of peripheral CD34 cells of high-dose etoposide permitted the collection of sufficient for all 16 patients are shown in Figure 3. + + numbers of CD34 cells in all 16 patients who had failed A comparison of CD34 cells was performed in five initial cyclophosphamide mobilization. The toxicity of eto- additional patients not included in this report who were suc- poside 2 g/m2 was mainly hematological, with WHO grade cessfully mobilized with cyclophosphamide. Interestingly, IV leukocytopenia and thrombocytopenia and with a rebound increase in PBSC showed higher peak values of median duration of 6.0 (3–9) and 6.0 (3–10) days, respect- CD34+ cells after etoposide as compared to cyclophos- ␮ = ively. Nonhematological toxicity was mild, with one WHO phamide (median: 37.2/ l vs 125.4; P 0.1441). grade III infection and moderate mucositis. Therefore, we Toxicity after high-dose etoposide was evaluable for all consider etoposide mobilization feasible without severe patients. Non-hematological toxicity was moderate with side-effects. After etoposide mobilization PBSC quality one WHO grade III infection due to septicemia in therapy- appeared not to be impaired. 13/16 patients were success- induced myelosuppression. All but one patient experienced fully transplanted with normal engraftment patterns. WHO grade IV leukocytopenia and thrombocytopenia with HDCT followed by autologous stem cell support is con- a median duration of 6.0 (range 3–9) and 6.0 (range 3– sidered the treatment of choice for patients with relapsed 10) days, respectively (Table 4). Platelet transfusions were or refractory NHL or HD as suggested by the results of necessary in 13/16 patients (median 2.0; range 0–4), and randomized trials performed by the PARMA group,18 the British National Lymphoma Investigation,19 and the Ger- 20 Table 4 Toxicity of etoposide 2 g/m2 + G-CSF according to the WHO man Hodgkin Study Group. Autologous stem cells are classification (total 16 cycles) routinely harvested by leukapheresis after chemotherapy- induced marrow aplasia with a target yield of Ͼ2.0 ϫ 106 + Toxicity WHO grade CD34 cells/kg. A variety of different mobilization regimens has been described. The combination of chemo- I II III IV therapy and growth factors such as G-CSF or GM-CSF is the most efficient way to mobilize stem cells.21 Myelosuppression In the present study, we report on a group of 16 heavily Leukocytopenia – — — 15a b pretreated lymphoma patients who failed initial mobiliz- Thrombocytopenia – — — 15 2 Anemia 0 6 8 1 ation with high-dose cyclophosphamide (4 g/m ) and G- CSF at a dose of 2 ϫ 5 ␮g/kg. All 16 patients were inten- Infections 6 2 1 sively pretreated with aggressive combination chemo- Fever — — 9c — therapy and a median of eight cycles (range 1–11) of differ- Nausea and vomiting 4 3 1 — Diarrhea 3 0 0 0 ent regimens. Six of 16 patients were refractory to prior Mucositis 10 1 — — treatment and 6/16 (38%) of the patients had prior radio- Cardiac function — — — therapy. In addition, although the DHAP regimen Pulmonal — — — — (dexamethasone, cytarabine, cisplatin) used in 11/16 Renal — — — — patients prior to cyclophosphamide does not consist of stem Neurotoxicity — — — — cell toxic drugs, the short interval between the two DHAP aDuration: median 6 days (3–9). cycles (median 16 days) may have adversely influenced bDuration: median 6 days (3–10). stem cell yields in these patients. Five of 16 patients cDuration: median 1 days (0–7). received Dexa-BEAM which contains the stem cell-toxic Successful PBSC mobilization with etoposide M Reiser et al 1227 drugs BCNU and melphalan. The number of Dexa-BEAM high-dose etoposide permitted the collection of sufficient cycles has been shown to be the predominate prognostic numbers of CD34+ cells in all patients. Even in one patient factor affecting CD34+ cell yield in a study of 96 patients who had failed cyclophosphamide mobilization after prior reported by Dreger et al.10 HDCT and radiotherapy, a second mobilization with etopo- High-dose cyclophosphamide followed by G-CSF has side allowed the harvest of a sufficient number of CD34+ gained favor as the preferred chemotherapy agent for mobi- cells. lization. The dose given varies from 1.5 to 7.0 g/m2 and Why etoposide mobilization resulted in a 100% success- 2–4 g/m2 is used by most groups. Although very effective ful harvest of PBSC in our patients remains unclear. There in the vast majority of patients, a substantial proportion of was no difference in the time interval between last induc- patients fail to mobilize adequate numbers of PBSC. Mobil- tion chemotherapy and cyclophosphamide mobilization (25 ization has been reported to be particularly difficult in days; range 19–147) and the time interval between cyclo- patients with relapsed or primary refractory lymphoma. phosphamide and etoposide mobilization (39 days; range Tarella et al8 assessed the mobilization of 48 patients with 25–65); P = 0.1554. Etoposide mobilization was successful non-Hodgkin’s lymphoma or Hodgkin’s disease. PBSC after a prior non-stem cell toxic regimen (DHAP) as well mobilization was significantly higher in patients at first as after a stem cell toxic regimen (Dexa-BEAM). Com- diagnosis compared with refractory and relapsed patients pared with cyclophosphamide, etoposide is less commonly (median peak values of CD34+ cells: 286/␮l vs 47/␮l, P = used as a component of conventional first-line therapy. 0.0001). Only 15/27 (56%) patients under salvage treatment Therefore etoposide may lack cross-resistance with cyclo- with HDCT were able to complete PBSC autografting. phosphamide, but there are no data from the literature con- McQuaker et al22 report a 29% failure to achieve adequate cerning an increased mobilization efficacy. Finally, side- mobilization in a group of 50 patients with relapsed or effects of high-dose cyclophosphamide and etoposide were resistant lymphoma after cyclophosphamide 3–4 g/m2. mainly hematological with a median duration of leukocyto- There is some evidence that higher doses of cyclophos- penia WHO grade IV of 5.0 and 6.0 days, respectively. phamide result in higher PBSC yields, and higher doses of Although only slightly more toxic, etoposide produced a G-CSF have a similar effect.23 Although cyclophosphamide significantly higher rebound increase in PBCS in all 7 g/m2 may represent a useful mean of increasing collection patients allowing the collection of at least 2.0 ϫ 106 CD34+ of PBSC, the toxicity is considerable with occurrence of in 44% of the patients with a single leukapheresis. fatal complications in 2/21 patients.24 The collection of In conclusion, our study is the first intraindividual com- bone marrow cells under general anesthesia may be suc- parison of the mobilization efficacy of cyclophosphamide cessful in some of those patients who have failed mobiliz- and etoposide in 16 patients with relapsed or resistant lym- ation of peripheral stem cells. Since ABMT has been shown phoma. Etoposide mobilized significantly more CD34+ cells to be inferior to PBSCT in terms of time to engraftment than cyclophosphamide. Furthermore, in all 16 patients and infectious complications,11,12 alternative mobilization who had failed initial cyclophosphamide mobilization, the strategies are needed. use of etoposide enabled us to collect sufficient numbers of There are few studies that compare the efficacy of PBSC CD34+ cells avoiding the collection of bone marrow under mobilization with different chemotherapy protocols. In general anesthesia. Etoposide 2 g/m2 is an effective and safe myeloma patients, 7 g/m2 cyclophosphamide was more mobilization regimen and may be used in patients who have effective as compared with 4 g/m2.25 In patients with breast failed standard cyclophosphamide 4 g/m2 mobilization. To cancer, combination chemotherapy regimens were superior evaluate further the role of etoposide in stem cell mobiliz- to single-agent cyclophosphamide for the mobilization of ation, a prospective randomized trial comparing the two CD34+ cells,26 and in lymphoma patients a combination of mobilization regimens is required. ifosphamide, etoposide, and epirubicin (IVE) resulted in a significantly higher median yield of CD34+ cells ϫ 6 (8.62 10 /kg) compared with cyclophosphamide plus G- References CSF (3.59 ϫ 106/kg) (P = 0.045).22 High-dose etoposide has been previously reported to be 27–29 27 1 Indovina A, Liberti G, Majolino I et al. Cyclophosphamide 4 effective in lymphoma patients. Copelan et al used 2 2 2 g/m plus rhG-CSF for mobilization of circulating progenitor g/m etoposide as a continuous infusion over 24 h in 169 cells in malignant lymphomas. Int J Artif Org 1993; 5: 30–34. patients with breast cancer, non-Hodgkin’s lymphoma, and 2 Rosenfeld CS, Shadduck RK, Zeigler ZR et al. Cyclophos- Hodgkin’s disease. The mobilization was effective in nearly phamide-mobilized peripheral blood stem cells in patient with all patients with moderate nonhematological toxicity. A lymphoid malignancies. Bone Marrow Transplant 1995; 15: 50% reduction of tumor size was seen in 44% of NHL and 433–438. 38% of HD patients. Watanabe et al28 used etoposide (500 3 Watts MJ, Sullivan AM, Jamieson E et al. Progenitor-cell mg/m2/day for 3 or 4 days) in patients with various malig- mobilization after low-dose cyclophosphamide and granulo- nancies. Total numbers of CD34+ cells obtained from mul- cyte colony-stimulating factor: an analysis of progenitor-cell tiple leukaphereses after 13 mobilization courses were quantity and quality and factors predicting for these para- meters in 101 pretreated patients with malignant lymphoma. mean 33.94 (range 0.63–168.74) ϫ 106/kg. Very recently, 30 J Clin Oncol 1997; 15: 535–546. Pucci et al reported their experience with three patients 4 Haas R, Mohle R, Fruhauf S et al. Patient characteristics asso- who had failed cyclophosphamide mobilization but who ciated with successful mobilizing and autografting of periph- were successfully mobilized with high-dose etoposide (2 eral blood progenitor cells in malignant lymphoma. Blood g/m2). In the 16 patients included in our study the use of 1994; 83: 3787–3794. Successful PBSC mobilization with etoposide M Reiser et al 1228 5 Tarella C, Caracciolo D, Gavarotti P et al. Circulating pro- 18 Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone genitors following high-dose sequential (HDS) chemotherapy marrow transplantation as compared with salvage chemo- with G-CSF: short intervals between drug courses severely therapy in relapses of chemotherapy-sensitive non-Hodgkin’s impair progenitor mobilization. Bone Marrow Transplant lymphoma. New Engl J Med 1995; 333: 1540–1545. 1995; 16: 223–228. 19 Linch DC, Winfield D, Goldstone AH et al. Dose intensifi- 6 Kotasek D, Shepherd KM, Sage RE et al. Factors affecting cation with autologous bone-marrow transplantation in blood stem cell collections following high-dose cyclophos- relapsed and resistant Hodgkin’s disease: results of a BNLI phamide mobilization in lymphoma, myeloma and solid randomised trial. Lancet 1993; 341: 1051–1054. tumors. Bone Marrow Transplant 1992; 9: 11–17. 20 Schmitz N, Sextro M, Hasenclever D et al. HD-R1 first results 7 Olivieri A, Offidani M, Ciniero L et al. PBSC collection after of a randomized trial comparing aggressive chemotherapy high-dose chemotherapy followed by G-CSF in patients with with high-dose therapy and hematopoietic stem cell transplan- malignancies: analysis of results regarding factors affecting tation in patients with chemosensitive relapse of Hodgkin’s the yield of hemopoietic progenitors. Int J Artif Org 1993; 5: disease. Blood 1997; 10 (Suppl. 1): 115a (Abstr.). 57–63. 21 Pettengell R, Testa NG, Swindell R et al. Transplantation 8 Tarella C, Castellino C, Cherasco C et al. Peripheral blood potential of hematopoietic cells released into the circulation progenitor cell mobilization in patients with primary refractory during routine chemotherapy for non-Hodgkin’s lymphoma. lymphoma or at first relapse: comparison with patients at diag- Blood 1993; 82: 2239–2248. nosis and impact on clinical outcome. Br J Haematol 1997; 22 McQuaker IG, Haynes AP, Stainer C et al. Stem cell mobiliz- 99: 41–46. ation in resistant or relapsed lymphoma: superior yield of pro- 9 Moskowitz CH, Glassman JR, Wuest D et al. Factors affecting genitor cells following a salvage regimen comprising ifos- mobilization of peripheral blood progenitor cells in patients phamide, etoposide and epirubicin compared to intermediate- with lymphoma. Clin Cancer Res 1998; 4: 311–316. dose cyclophosphamide. Br J Haematol 1997; 98: 228–233. 10 Dreger P, Kloss M, Petersen B et al. Autologous progenitor 23 Zeller W, Gutensohn K, Stockschlader M et al. Increase of cell transplantation: prior exposure to stem cell-toxic drugs mobilized CD34-positive peripheral blood progenitor cells in determines yield and engraftment of peripheral blood progeni- patients with Hodgkin’s disease, non-Hodgkin’s lymphoma, tor cell but not of bone marrow grafts. Blood 1995; 86: and cancer of the testis. Bone Marrow Transplant 1996; 17: 3970–3978. 709–713. 11 Liberti G, Pearce R, Taghipour G et al. Comparison of periph- 24 Indovina A, Majolino I, Scime R et al. High dose cyclophosphamide: stem cell mobilizing capacity in 21 patients. Leuk eral blood stem-cell and autologous bone marrow transplan- Lymphoma 1994; 14: 71–77. tation for lymphoma patients: a case-controlled analysis of the 25 Goldschmidt H, Hegenbart U, Haas R, Hunstein W. Mobiliz- EBMT Registry data. Lymphoma Working Party of the ation of peripheral blood progenitor cells with high-dose EBMT. Ann Oncol 1994; 2: 151–153. cyclophosphamide (4 or 7 g/m2) and granulocyte colony-sti- 12 Schmitz N, Linch DC, Dreger P et al. Randomised trial of mulating factor in patients with multiple myeloma. Bone Mar- filgrastim-mobilised peripheral blood progenitor cell trans- row Transplant 1996; 17: 691–697. plantation versus autologous bone-marrow transplantation in 26 Demirer T, Buckner CD, Storer B et al. Effect of different lymphoma patients. Lancet 1996; 347: 353–357. chemotherapy regimens on peripheral-blood stem-cell collec- 13 Engert A, Josting A, Mapara M et al. High-dose sequential tions in patients with breast cancer receiving granulocyte col- chemotherapy and autologous stem cell support for relapsed ony-stimulating factor. J Clin Oncol 1997; 15: 684–690. or refractory Hodgkin’s and non-Hodgkin’s lymphoma – first 27 Copelan EA, Ceselski SK, Ezzone SA et al. Mobilization of results from an ongoing multicenter pilot study. Leuk Lym- peripheral-blood progenitor cells with high-dose etoposide and phoma 1998; 29 (Suppl. 1): 152 (Abstr.). granulocyte colony-stimulating factor in patients with breast 14 Pfreundschuh MG, Rueffer U, Lathan B et al. Dexa-BEAM cancer, non-Hodgkin’s lymphoma, and Hodgkin’s disease. J in patients with Hodgkin’s disease refractory to multidrug Clin Oncol 1997; 15: 759–765. chemotherapy regimens: a trial of the German Hodgkin’s Dis- 28 Watanabe S, Mukaiyama T, Ogawa Y et al. Peripheral blood ease Study Group. J Clin Oncol 1994; 12: 580–586. stem cell mobilization with chemotherapy and granulocyte- 15 Josting A, Katay I, Rueffer U et al. Favorable outcome of colony stimulating factor in patients with hematological patients with relapsed or refractory Hodgkin’s disease treated malignancies. Tokai J Exp Clin Med 1994; 19: 143–155. with high-dose chemotherapy and stem cell rescue at the time 29 Gianni AM, Bregni M, Siena S et al. Granulocyte–macro- of maximal response to conventional salvage therapy (Dexa- phage colony-stimulating factor or granulocyte colony-stimul- BEAM). Ann Oncol 1998; 9: 289–295. ating factor infusion makes high-dose etoposide a safe out- 16 Bender JG, Unverzagt KL, Walker DE. Identification and patient regimen that is effective in lymphoma and myeloma comparison of CD34 positive cells and their subpopulations patients. J Clin Oncol 1992; 10: 1955–1962. from normal peripheral blood and bone marrow using multi- 30 Pucci G, Irrera G, Martino M et al. High-dose etoposide color flow cytometry. Blood 1991; 77: 2591–2596. enables the collection of peripheral blood stem cells in patients 17 Leary AG, Ogawa M, Strauss LC. Single cell origin of multi- who failed cyclophosphamide-induced mobilization. Br J lineage colonies in culture. J Clin Oncol 1984; 84: 2193–2196. Haematol 1998; 100: 612–613.