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

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 metast atic breast cancer undergoing a sequential high-dose paclitaxel, melphalan, and cyclophosphamide, thiotepa, and carboplatin (CTCb) chemotherapy regime n were evaluated. The intertreatment interval was a median of 27 days. Pacl itaxel was escalated from 400 to 825 mg/m(2), infused continuously (CI) ove r 24 h on day -4 with PBPC reinfusion on day 0. Following marrow recovery, 90 mg/m(2)/day of melphalan was given over 30 min on days -2 and -1, with P BPC 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 10(9)/L occurred at a me dian of 6 days (range 0-7 days) after PBPC reinfusion. The median nadir pla telet count was 63 x 10(9)/L (range 6 x 10(9)/L-176 x 10(9)/L). Eight patie nts (12%) had platelet nadir <20 x 10(9)/L, and all recovered their counts to >20 x 10(9)/L on day 7. There was no clinical difference in days to engr aftment between women receiving <2 or greater than or equal to 2 x 10(6) CD 34(+) PBPC/kg following paclitaxel. All patients recovered neutrophil and p latelet counts within 7 days after reinfusion of II x 106 CD34(+) cells/kg and G-CSF. The data suggest that a paclitaxel dose of 825 mg/m(2) is not my eloablative. For melphalan, median days to ANC >0.5 x 10(9)/L was 10 days ( range 9-15), and platelet recovery to >20 x 10(9)/L was 13 days (range 0-28 ) after PBPC reinfusion. Median time to engraftment was more rapid in patie nts receiving greater than or equal to 2 x 10(6) CD34(+)/kg versus <2 x 10( 6) CD34(+)/kg, for both neutrophils (11 days versus 10 days, p = 0.05) and platelets (14 days versus 12 days, p < 0.01). Ninety-eight percent of patie nts infused with greater than or equal to 2 x 10(6) CD34(+)/kg engrafted wi thin 21 days. Following CTCb in this sequential regimen, a dose of greater than or equal to 2 x 10(6) CD34(+) cells/kg provided for significantly more rapid neutrophil engraftment than <2 x 10(6) CD34(+) cells/kg (9 days vers us 10 days, p = 0.01), but a dose greater than or equal to 3 x 10(6) CD34() cells/kg is necessary for reliable, rapid, and sustained neutrophil and p latelet engraftment by day 21.