Very large amounts of peripheral blood progenitor cells eliminate severe thrombocytopenia after high-dose melphalan in advanced breast cancer patients

Abstract

We analyzed the relationship between the reinfusion of large or very large amounts of peripheral blood progenitor cells (PBPC) and hematologic toxicity in twenty-one advanced breast cancer patients subjected to a myeloablative dose of melphalan at the end of a high-dose sequential chemotherapy (HDSC) program. We also evaluated the influence of the white blood cell (WBC) count to predict an optimal PBPC harvest after high-dose chemotherapy and growth factor priming. Twenty-one patients with high-risk or metastatic breast cancer sequentially received: high-dose cyclophosphamide (HD-Cy) and G-CSF followed by PBPC harvest, HD-methotrexate plus vincristine, HD-doxorubicin, cisplatin and finally HD-melphalan 200 mg/m² (HD-L-PAM) followed by PBPC reinfusion. No growth factor was administered after HD-L-PAM. CD34⁺ cytofluorimetric analysis, WBC count and clonogenic assays were employed to monitor circulating cells and to analyze the PBPC harvest. Correlation between different PBPC doses and hematologic toxicity as well as leukocyte and platelet recovery time was attempted. Patients received a median number of 16 (4–25.1) × 10⁶/kg CD34⁺ cells, 81.3 (30.8–228) × 10⁴/kg CFU-GM and 4.2 (1.3–7.3) × 10⁸/kg nucleated cells (NC) after HD-L-PAM. The number of days with fewer than 1 × 10⁹/l leukocytes and 20 × 10⁹/l platelets were 6 (range 4–9) and 0 (range 0–3), respectively. The CD34⁺ cell dose significantly correlated with both platelet count nadir (r = 0.73) and time to 50 × 10⁹/l platelets (r = 0.7), but did not correlate with time to reach more than 1 × 10⁹/l WBC count (r = 0.2). In particular, we found that in 12 patients given very large amounts of CD34⁺ cells, ranging between 15.8 and 25.1 × 10⁶/kg (V-LA-CD34⁺), the platelet nadir count never fell below 20 × 10⁹/l and platelet transfusions were not required. Conversely, nine patients who received only large amounts of CD34⁺ cells, ranging between 4 and 12 × 10⁶/kg (LA-CD34⁺), experienced a platelet nadir lower than 20 × 10⁹/l and required 2 days (range 1–4) to achieve independence from platelet transfusions (P = 0.001 and P = 0.0005). The requirement for packed red blood cells (RBC) was 1.5 vs 3 units in the V-LA-CD34⁺ and LA-CD34⁺ groups respectively (P = 0.063). The analysis of 44 PBPC collections demonstrated that 29 aphereses performed with a WBC count <20 × 10⁹/l yielded a mean of 312 ± 43 × 10⁶ CD34⁺ cells and 1831 ± 201 × 10⁴ CFU-GM, whereas 15 collections performed with WBC count >20 × 10⁹/l yielded 553 ± 64 × 10⁶ CD34⁺ cells and 3190 ± 432 × 10⁴ CFU-GM (P = 0.004). In conclusion, our data suggests that V-LA-CD34⁺ eliminates severe thrombocytopenia and platelet transfusion requirements in breast cancer patients subjected to HD-L-PAM, and higher PBPC collections seems to coincide with WBC count higher than 20 × 10⁹/l after HD-Cy and G-CSF mobilization. These results justify a prospective study to establish whether large doses of CD34⁺ cells result in significant clinical benefits.