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 CD346+ 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 1066 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). Ninety-eight percent of patients infused with ≥2 x 10⁶ CD346+/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.