Cyclophosphamide and Paclitaxel As Initial Or Salvage Regimen for the Mobilization of Peripheral Blood Progenitor Cells
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Bone Marrow Transplantation, (1999) 24, 959–963 1999 Stockton Press All rights reserved 0268–3369/99 $15.00 http://www.stockton-press.co.uk/bmt Cyclophosphamide and paclitaxel as initial or salvage regimen for the mobilization of peripheral blood progenitor cells JL Klein, PM Rey, R Dansey, C Karanes, E Abella, L Cassells, C Hamm, M Flowers, C Couwlier, WP Peters and RD Baynes Bone Marrow Transplantation, Division of Hematology and Oncology, Barbara Ann Karmanos Cancer Institute, and Wayne State University, Detroit, MI, USA Summary: accelerate the tempo of engraftment compared to bone mar- row cells, thereby reducing morbidity, mortality, support Peripheral blood progenitor cells are now commonly measures required and economic costs.1–4 In addition, used for hematologic reconstitution after myelosup- PBPCs can be collected in an outpatient setting with mini- pressive chemotherapy for hematologic and solid malig- mal morbidity avoiding the operative procedure of BM har- nancies. The purpose of this study was to evaluate the vest. Hematopoietic growth factors alone can provide an activity of paclitaxel 170 mg/m2 and cyclophosphamide adequate yield of stem cells to ensure hematological recon- 2 g/m2 (CP) with filgrastim (human G-CSF) for mobiliz- stitution after HDC. Collection of PBPCs after CT followed ation of PBPCs as the first or second maneuver after by cytokines takes advantage of the additional mobilizing failure with filgrastim alone. Sixty-four patients with effect of the myelosuppressive drugs. The use of chemo- stage II–IV breast cancer received (CP) followed by fil- therapy has been recognized to increase PBPC yields com- grastim (10 g/kg/day). In 35 (55%) this was the first pared to cytokines alone, therefore requiring fewer apher- maneuver while it was for salvage in 29 (45%) patients. esis procedures.5,6 In spite of the extensive experience The median number of aphereses was two (range, 1–7). acquired in this area, it is not known which is the best In 83% of the patients apheresis was initiated on days regimen to mobilize hematopoietic progenitor cells. Mobil- 10–11 following chemotherapy. The median numbers of ization with disease-oriented chemotherapy together with CD34+ cells/kg, CD34+ cells/apheresis/kg and total cytokines may be also combine the advantage of antitumor nucleated cells/kg collected were 8.7 × 106 (2.11–73.5), activity with PBPC mobilization.7,8 Paclitaxel and cyclo- 3.97 × 106 (0.3–36.75) and 164.15 × 108 (9–660), respect- phosphamide are both active in breast cancer and share a ively. All the patients yielded at least 2 × 106 CD34+ similar pattern of hematological recovery. The value of a cells/kg. CP mobilization salvaged the 29 patients who combination of paclitaxel and cyclophosphamide as a mob- failed mobilization with filgrastim alone. When used as ilization regimen in patients with ovarian and breast cancer first-line mobilization the yield of CD34+ cells × 106/kg has already been described.9,10 was higher than in the salvage group (16.93 vs 3.94, One of the problems associated with the use of PBPCs P Ͻ 0.001). Patients receiving CP as salvage reached the is the variability in the number of cells collected between target of 5 × 106 CD34+ cells/kg in only 45% (13/29) of patients, partly because of the amount of previous treat- cases vs 94.3% as first maneuver. CP followed by fil- ment.11–14 Moreover, cytokines by themselves will fail to grastim is a safe and effective regimen for the mobiliz- mobilize stem cells in 10% of patients.5,11,15 Some of these ation of PBPCs in patients with breast cancer and shows patients still will be salvaged adding chemotherapy, higher significant activity in patients who failed to mobilize doses of growth factors or both, but the ideal salvage with filgrastim, suggesting a higher mobilization regimen is controversial.16 potential. Our report studies the efficacy of paclitaxel 170 mg/m2 Keywords: PBPC; mobilization; CD34 selection; Isolex and cyclophosphamide 2 g/m2 (CP) with filgrastim, and 300i particularly analyzes its value as a salvage maneuver after failure to mobilization by filgrastim alone. Within the last decade mobilized peripheral blood progeni- Patients and methods tor or stem cells (PBPC) have emerged as the most common source of hematopoietic cells for support following high- dose chemotherapy (HDC). Various combinations of cyto- Patients kines or myelosuppressive chemotherapy (CT) and cyto- Between November 1996 and January 1998 64 women with kines have been used to mobilize PBPCs. PBPC infusions stage II–IV breast cancer underwent PBPC collection after paclitaxel 170 mg/m2 and CP 2 g/m2 followed by subcut- Correspondence: Dr JL Klein, Karmanos Cancer Institute, 3990 John R, aneous filgrastim. Thirty-five (55%) patients were mobil- 4 Brush South, Detroit, Michigan 48201, USA ized in this fashion as first maneuver, and 29 (45%) after Received 11 March 1999; accepted 23 June 1999 a prior, unsuccessful attempt with filgrastim 10 g/kg alone PBPC mobilization with cyclophosphamide/paclitaxel JL Klein et al 960 (45%) (Table 1). Thirty-two patients who had either bone 20 mg i.v., diphenhydramine 50 mg i.v. and cimetidine marrow involvement or multiple skeletal metastasis were 300 mg i.v. 20 min before paclitaxel administration. Cyclo- involved in a protocol for CD34 selection as a means of phosphamide 2.0 g/m2 was given intravenously 1 h after the tumor purging and had CD34 positive enrichment of the completion of the paclitaxel. Cyclophosphamide was PBPC production after collection using the Isolex 300i infused over 1 h. All patients received MESNA for the pre- (Baxter Healthcare Corporation, Irvine, CA, USA). Patients vention of hemorrhagic cystitis. The MESNA dose was could have received prior chemotherapy for metastatic dis- 2.0 g/m2 as equally divided administrations prior to ease. As part of this protocol, patients underwent initial infusion of CP and 4 and 8 h after. Following chemotherapy PBPC mobilization with CP. Three additional patients with patients received filgrastim 10 g/kg/day subcutaneously. high risk primary breast cancer either stage II (one) or III Patients also received ciprofloxacin, 500 mg three times a (two) received CP as the initial mobilization regimen. day as bacterial prophylaxis. These patients had mobilization with CP because of delays in obtaining insurance coverage and received chemotherapy Collection and cryopreservation of PBPC because of the length of time since their last chemotherapy. Patients who were initially mobilized with filgrastim but Following the administration of the chemotherapy and fil- did not produce 2.5 × 106 CD34+/kg underwent salvage grastim, patients had complete blood counts measured mobilization. Patients given filagrastim had received every other day and began apheresis when the WBC count 10 g/kg for 4 days. On the fifth day PB CD34+ cells were was at least 1.5 × 109/ml. Daily apheresis procedures were enumerated by FACS analysis. Patients with Ͼ10/l were performed using a Fenwall CS 3000 plus cell separator started on leukapheresis and continued for 3 days. If the (Fenwall, Baxter Healthcare Corporation, Round Lake, IL, PB CD34+ cell count was Ͻ10 l, patients were continued USA). Sixteen liters were processed per procedure, using on filgrastim and PB CD34+ cells were again checked. If continuous flow centrifugation at a flow rate of 70 ml/min. the PB CD34+ cells remained below 10/l for 3 days they The target was to collect у5.0 × 106 CD34+ cells/kg, but were considered mobilization failures and proceeded to CP attempts were made to collect a minimum of 2.5 × 106 mobilization. Patients who had Ͼ10 CD34+ cells/l and cells/kg. The final product containing 10% DMSO and started PBPC collection but did not yield Ͼ2.5 × 106 CD34+ autologous plasma was frozen in a liquid nitrogen con- cell/kg within 3 days and had a falling PB CD34+ cell count trolled-rate freezer and was maintained in the liquid phase were also considered mobilization failures and proceeded of liquid nitrogen. to CP mobilization. No patients received a second mobiliz- ation with filgrastim at either the same or an increased dose. High-dose chemotherapy regimens Five of the women who received CP, as the second mobiliz- ation regimen had stage II disease and 24 (83%) had stage All but three patients received cisplatin, CP and BCNU IV disease. The median number of chemotherapy cycles (STAMP I) followed by PBPC infusion. either adjuvantly and/or for metastatic disease was 10 (range, 3–26) and eight (range, 3–24), for patients under- Cyclophosphamide, cisplatin and BCNU: Sixty-one going mobilization as a first or salvage maneuver, patients received cyclophosphamide (1875 mg/m2/day) respectively. days −6to−4, cisplatin (165 mg/m2) continuous i.v. infusion days −6to−4, and BCNU (600 mg/m2) on day − Mobilization 3, as follows. Actual body weight was used to calculate the therapeutic doses of all agents unless the actual body On day 1 paclitaxel 170 mg/m2 was diluted in 500 cc D5W weight was 20% greater than the ideal body weight. In the in a glass container with a polyethylene-line tubing and a event that the actual body weight was 20% greater the aver- 0.22 m in-line filter and infused over 24 h intravenously. age of the ideal and actual body weight was used to calcu- Patients were premedicated with dexamethasone 20 mg late the therapeutic doses. PBPCs were reinfused 3 days orally 12 and 6 h before paclitaxel and dexamethasone after the completion of the regimen. Patients received fil- Table 1 Patient characteristics Overall Initial maneuver Salvage regimen n (%) 64 35 (55%) 29 (45%) Age (median and range) 47 (22–71) 45 (22–59) 48 (26–71) Stage II 6 (9.5%) 1 (3%) 5 (17%) III 2 (3%) 2 (6%) 0 IV 56 (87.5%) 32 (91%) 24 (83%) Prior radiotherapy 36 (56%) 16 (46%) 20 (69%) No.