Bone Marrow Transplantation, (1999) 23, 311–315 1999 Stockton Press All rights reserved 0268–3369/99 $12.00 http://www.stockton-press.co.uk/bmt A phase I study of paclitaxel for mobilization of peripheral blood progenitor cells BA Burtness1, A Psyrri2, M Rose1, E D’Andrea3, C Staugaard-Hahn4, M Henderson-Bakas1, MB Clark3, S Mechanic5, D Krause5, E Snyder5, RB Cooper6, J Abrantes7, R Corringham8, A Deisseroth1 and DL Cooper1 1Department of Internal Medicine, and 3Yale Cancer Center, Yale University School of Medicine; 5Blood Bank, and 4Department of Nursing, Yale-New Haven Hospital; 2Department of Internal Medicine, Hospital of St Raphael, New Haven, CT; 6Department of Internal Medicine, and 7Department of Nursing, Danbury Hospital, Danbury, CT; and 8University of California at San Diego Cancer Center, San Diego, CA, USA Summary: undergo apoptosis than are CD34ϩ cells in the peripheral blood in the unstimulated state.3 Non-randomized compari- We conducted a phase I trial to determine the dose and sons suggest that hematopoietic recovery will be shortened schedule of paclitaxel, when given together with filgras- after infusion of peripheral blood progenitor cells harvested tim, which would optimally promote mobilization of during filgrastim-supported recovery from chemotherapy.4,5 stem cells with tolerable toxicity. Dose escalation began There is an inverse relationship between yield and prior at 275 mg/m2 3 h infusion. Dose-limiting neuropathy treatment with radiotherapy and chemotherapy, and this is was observed at the 300 mg/m2 dose level. A second dose the most important predictive factor for yield. Among escalation was conducted utilizing 24 h infusion sched- patients with relapsed breast cancer, prior adjuvant therapy ules, beginning at 225 mg/m2. Dose escalation was con- and radiotherapy may impair mobilization. In addition, the tinued by 25 mg/m2 increments to 300 mg/m2, at which recent trend towards greater use of double or multicycle dose neuropathy was again dose-limiting. The rec- high-dose therapy, and use of purging systems which may ommended dose and schedule of paclitaxel for the pur- reduce cell number, have created a need for higher stem pose of mobilization of stem cells, when given together cell yields. Use of chemotherapy to aid in the mobilization with filgrastim, are 275 mg/m2 as a 24 h infusion. The of stem cells had been reported by Brugger et al6 to mobil- median stem cell yield after this dose of paclitaxel was ize epithelial cells in a time-dependent manner, but sub- ؋ 106 CD34؉ cells/kg/apheresis (range 3.6 ؋ 106 – sequent investigators have found no significant difference 6.6 ؋ 106). in contamination of progenitor cells mobilized by filgrastim 7.7 Keywords: breast neoplasm; mobilization; stem cells; alone compared with an historical group mobilized with paclitaxel high-dose cyclophosphamide followed by GM-CSF.7 Paclitaxel contributes to mobilization in combination with high-dose cyclophosphamide, epirubicin, or cyclopho- sphamide and etoposide.8–13 Paclitaxel as a single agent has Peripheral blood progenitor cells are now preferred to bone potential advantages over the high-dose and combination marrow for hematopoietic reconstitution after high-dose mobilizing regimens in current use: it rapidly induces a leu- chemotherapy because they are associated with shorter per- kocyte nadir which is of brief duration, does not cause sev- iods of cytopenia and fewer acute complications. Rapid ere thrombocytopenia, is active at standard doses against hematopoietic recovery following stem cell infusion ren- the malignancies for which high-dose chemotherapy is most ders multicycle high-dose chemotherapy feasible, which often considered, and has less toxicity than high-dose and has led to improvements in complete response rates in the combination regimens. It can be used safely in the setting 1 treatment of metastatic breast cancer. The risk of reintro- of doxorubicin-induced cardiomyopathy.14 We conducted ducing malignant cells may be reduced with the use of the current phase I study to determine the optimum dose 2 peripheral blood stem cells, compared with bone marrow. and schedule of paclitaxel alone to promote a high circulat- The optimal means of mobilizing peripheral blood stem ing CD34ϩ cell count and permit stem cell harvesting. cells is not known. Adequate numbers of stem cells, esti- mated by CD34ϩ cell determination, can be obtained by apheresis after administration of colony-stimulating factors Materials and methods or during rebound leukocytosis after moderately or severely myelosuppressive chemotherapy. CD34ϩ cells collected after the use of filgrastim are significantly less likely to Patient selection Patients were eligible if they were already receiving paclit- Correspondence: Dr BA Burtness, Yale University School of Medicine, axel chemotherapy and were candidates to receive high- 333 Cedar Street, PO Box 208032, New Haven, CT 06520–8032, USA dose chemotherapy with peripheral blood stem cell rescue. Received 26 March 1998; accepted 23 September 1998 Patients with advanced breast, ovarian and testicular cancer Phase I study of paclitaxel for mobilization BA Burtness et al 312 were eligible. Other requirements were an ECOG perform- whichever was closer to 5 ␮g/kg, and was administered ance status of 0 or 1, age у18 years, absolute neutrophil subcutaneously. A CBC was performed on alternate days count of 1500/␮l, platelet count of 100 000/␮l, and infor- until the nadir and then daily to the conclusion of leukaph- med, written consent. The consent form was approved by eresis. Prophylactic ciprofloxacin 500 mg p.o. was adminis- the Yale University Human Investigation Committee, the tered twice daily when the neutrophil count was Danbury Hospital Institutional Review Board, and the Ͻ1 ϫ 109/l. If neutropenic fever developed during cipro- UCSD Institutional Review Board. Patients were excluded floxacin prophylaxis, patients were hospitalized for intra- if they had demonstrated life-threatening hypersensitivity to venous broad-spectrum antibiotics. previous doses of paclitaxel, had received prior mitomycin, Leukapheresis was commenced upon recovery of the cisplatin or nitrosourea chemotherapy, had brain metastases white blood cell count from its nadir, or upon CD34ϩ count or had received radiotherapy to the brain, or had other seri- greater than 20 cells/nl. Absence of fever and recent nega- ous active medical or psychiatric disease. Patients were also tive blood culture were also required before leukapheresis excluded if they had received more than 500 mg/m2 of an for patients who had required treatment for neutropenic anthracycline, had an ejection fraction of Ͻ40%, or had fever. The mononuclear cell collection procedure was per- wall motion abnormalities. These exclusions were made formed with either a CS-3000 plus blood cell separator because we were not routinely offering stem cell trans- (Baxter, Fenwall Division, Round Lake, IL, USA) or a plantion to patients with cardiomyopathy, and not because COBE Spectra (COBE BCT, Lakewood, CO, USA). The cardiomyopathy is an absolute contraindication to the use procedures were performed using an appropriate central of paclitaxel at these doses. Patients could not be pregnant, venous access catheter. Collections using the CS-3000 plus be within the first 2 weeks after major surgery, or have a were performed according to the manufacturer’s protocol history of prior malignancy, except for cervical carcinoma (special procedure 1–4), with the flow rate adjusted based in situ or non-melanoma skin cancer. on hematocrit. Cells were collected at 60–80 ml/min for a total of 12 l blood processed. For collection on the COBE Treatment plan spectra, the ‘MNC’ procedure was selected. All patients after patient No. 3 received prophylactic calcium gluconate Pre-treatment evaluation consisted of history and physical infusion intravenously. examination, chest radiograph, electrocardiogram, equilib- Of the 24 patients enrolled, 21 underwent high-dose rium radionuclide angiography, MR of the brain, complete chemotherapy with stem cell reinfusion. Two patients did blood count (CBC), serum chemistries, bone marrow aspir- not proceed with high-dose chemotherapy because of pro- ation and biopsy, urinalysis and creatinine clearance. gression of disease that occurred between stem cell collec- A double-lumen central vascular access device suitable tion and the scheduled start of high-dose chemotherapy. for leukapheresis was inserted and the patients were One did not because of inadequate mobilization despite instructed in catheter care. Patients received dexamethasone repeated attempts. One patient received a single cycle of 20 mg p.o. 14 and 7 h prior to paclitaxel. Paclitaxel was combination cyclophosphamide, thiotepa and carboplatin administered intravenously with cimetidine and diphenhyd- with stem cell support; a second received a single cycle of ramine premedication. For patients on the first two dose high-dose melphalan; a third tandem transplant consisting levels, this was as a 3 h infusion in the outpatient depart- of high-dose carboplatin, mitoxantrone and cyclophos- ment. For patients on the subsequent dose levels, this was phamide in the first cycles and carboplatin, etoposide and as a 24 h infusion via an ambulatory infusion device. thiotepa in the second; and the remainder of the patients The initial dose was 275 mg/m2, based on actual body received sequential single-agent high-dose therapy with weight. For patients more than 40% above ideal body melphalan 140 mg/m2 for the