CD34+ Cell Dose Requirements for Rapid Engraftment in a Sequential High-Dose Chemotherapy Regimen of Paclitaxel,Melphalan,and Cyclophosphamide,Thiotepa,and Carboplatin (CTCb) with PBPC Support in Metastatic Breast Cancer

Abstract

Sequential high-dose chemotherapy may increase the threshold dose of CD34+ cells necessary for rapid and successful hematologic recovery. There are limited data regarding the pharmacodynamics and threshold CD34+ cell dose required for engraftment following high-dose paclitaxel. To determine the dose of CD34+ PBPC sufficient for rapid engraftment, 65 women with metastatic breast cancer undergoing a sequential high-dose paclitaxel, melphalan, and cyclophosphamide, thiotepa, and carboplatin (CTCb) chemotherapy regimen were evaluated. The intertreatment interval was a median of 27 days. Paclitaxel was escalated from 400 to 825 mg/m2, infused continuously (CI) over 24 h on day - 4 with PBPC reinfusion on day 0. Following marrow recovery, 90 mg/m2/day of melphalan was given over 30 min on days - 2 and - 1, with PBPC reinfusion on day 0. On recovery, patients received CTCb on days - 7 to - 3, with PBPC reinfusion on day 0. G-CSF was administered after each cycle until WBCC recovery. For paclitaxel, an ANC > 0.5 X 109/L occurred at a median of 6 days (range 0-7 days) after PBPC reinfusion. The median nadir platelet count was 63 X 109/L (range 6 X 109/L-176 X 109/L). Eight patients (12%) had platelet nadir < 20 X 109/L, and all recovered their counts to > 20 X 109/L on day 7. There was no clinical difference in days to engraftment between women receiving < 2 or >= 2 X 106 CD34 + PBPC/kg following paclitaxel. All patients recovered neutrophil and platelet counts within 7 days after reinfusion of >= 1 X 106 CD34 + cells/kg and G-CSF. The data suggest that a paclitaxel dose of 825 mg/m2 is not myeloablative. For melphalan, median days to ANC > 0.5 X 109/L was 10 days (range 9-15), and platelet recovery to > 20 X 109/L was 13 days (range 0-28) after PBPC reinfusion. Median time to engraftment was more rapid in patients receiving >= 2 X 106 CD34 + /kg versus < 2 X 106 CD34 + /kg, for both neutrophils (11 days versus 10 days, p = 0.05) and platelets (14 days versus 12 days, p < 0.01). Ninetyeight percent of patients infused with >= 2 X 106 CD34 + /kg engrafted within 21 days. Following CTCb in this sequential regimen, a dose of >= 2 X 106 CD34 + cells/kg provided for significantly more rapid neutrophil engraftment than < 2 X 106 CD34 + cells/kg (9 days versus 10 days, p = 0.01), but a dose >= 3 X 106 CD34 + cells/kg is necessary for reliable, rapid, and sustained neutrophil and platelet engraftment by day 21.