A Mobilizing Regimen of AMD3100 and G-CSF Increases Stem Cell Collection in Patients with Hodgkin’s Disease, and PK Is Similar to That of Non-Cancer Patients.

Abstract

Abstract For patients undergoing autologous peripheral blood stem cell transplantation (PBSCT), the number of CD34+ cells collected is a reliable predictor of neutrophil and platelet engraftment after transplantation, with doses > 5 x 106 CD34+ cells/kg associated with faster count recovery. Unfortunately, collection of an adequate number of peripheral blood stem cells (PBSCs) can be difficult in Hodgkin’s disease (HD) patients. AMD3100 reversibly inhibits the binding of stromal cell-derived factor 1 (SDF-1), constitutively expressed on bone marrow stromal cells, to its receptor CXCR4, expressed on CD34+ cells. AMD3100 combined with G-CSF has been shown to improve PBSC collection compared to mobilization with G-CSF alone in patients with multiple myeloma or non-Hodgkin’s lymphoma (Blood2005;106:1867). This study was undertaken to determine whether a mobilization regimen of AMD3100 + G-CSF can safely and effectively mobilize PBSCs in patients with HD who are undergoing autologous PBSCT. Results were compared to a historical control group comprised of 98 consecutive HD patients who underwent G-CSF-alone mobilization at our institution. Patients were followed post-transplant to evaluate engraftment timing and durability. Pharmacokinetic (PK) determinations were completed in a subset of patients (n=6) following the first dose of AMD3100. To date, 19 patients with relapsed (17) or refractory (2) HD have been mobilized with G-CSF (10 ug/kg/d) + AMD3100 (240 ug/kg/d sc at 10 p.m. beginning on day 4). Apheresis was performed 11 hours after each AMD3100 dose. The first dose of AMD3100 produced a median (range) 3.0 (1.9–12) fold increase in the number of circulating CD34+ cells. Twelve patients (63%) achieved a collection of ≥ 5 x 106 CD34+ cells/kg, a significantly higher proportion than historical controls (15%, p=0.049). Eighteen patients (95%) mobilized with AMD3100 + G-CSF collected > 2 x 106 CD34+ cells/kg (range, 0.9–9.6 x 106 CD34+ cells/kg), compared to 78% of controls (p=0.116). The median (range) number of apheresis procedures performed per patient was 2 (1–5). The median collection in the first two days of pheresis was 5.0 x 106 CD34+ cells/kg, which is significantly better than historical controls, who collected a median 3.0 x 106 CD34+ cells/kg in the first two days of pheresis (p=0.002). No grade II-IV adverse events were ascribed to AMD3100. Eighteen patients were transplanted with G-CSF + AMD3100 mobilized cells. All had prompt and stable engraftment, with median neutrophil recovery at day +9 (8–11) and median platelet recovery at day +15 (9–20). PK studies demonstrated that AMD3100 was rapidly absorbed following subcutanetous injection, with a median (range) Cmax of 0.87 (0.66–1.16) ug/ml. Plasma concentrations declined in a bi-exponential manner, with a median elimination half-life of 3.7 (2.4–4.0) hours. The median AUC0–infinity was 3,749 (2,808–4,761) ug-hr/ml. AMD3100 pharmacokinetics in this patient population are consistent with results previously obtained from healthy volunteers in the absence of G-CSF. We conclude that AMD3100 + G-CSF is a well-tolerated and effective mobilization regimen in patients with HD. For these patients, AMD3100 + G-CSF can improve the number of PBSCs collected and decrease the number of days of pheresis.