AMD3100 Combined with Standard Doses of G-Csf Leads to Rapid, Consistent Mobilization of Hematopoietic Progenitor Cells in Patients with Non-Hodgkin's Lymphoma (NHL) and Multiple Myeloma.

Abstract

CXCR4, the chemokine receptor for stromal derived factor-1 (SDF-1) plays an important role in the homing and migration of hematopoietic stem cells. Selective inhibition of the binding of the CXCR4 receptor by the molecule AMD3100 leads to the mobilization of hematopoietic progenitors, including CD34+ cells into the circulation, even in the steady state. Preliminary studies have indicated that AMD3100 given 10–11 hours before each apheresis along with standard doses of G-CSF mobilizes more CD34+ cells per kilogram than does G-CSF alone. A Phase II study of this combination in patients with NHL and myeloma is underway. G-CSF at 10μg/kg/day for a duration of up to 9 days is administered with AMD3100 at 240 μg/kg/day starting on the evening of day 4 of G-CSF therapy, (10–11 hours prior to first and subsequent daily aphereses) until 5 x 106 CD34/kg are collected, or for a maximum of 5 days of a standard 3 blood volume apheresis. Both agents are administered subcutaneously. To date 20 patients (myeloma-6, NHL-14) have been enrolled and analyzed. Of these 20, 14 are considered to have been ‘heavily pre-treated' using standard definitions (≥ 10 cycles of chemotherapy, platinum based salvage chemotherapy and/or radiation therapy to bone marrow sites). Blood CD34 assays (cells/μl) were performed before and after each AMD 3100 dose and on each apheresis product. After the first dose of AMD3100 there was a 2.6 fold increase in CD34/μl in blood (23 → 60 CD34+ cells/μl). The median number of apheresis performed was 2 (range 1–5); the median total CD34 collected for all 20 patients was 5.7 x 106/kg (range 2.32–14.58 x 106/kg). All patients had collections of > 2.0 x106 CD34/kg, and in 12 of 20 the 5 x 106 CD34/kg cell dose goal was collected, including 8 of 14 in the heavily pre-treated group. In fact in 6, the 5 x 106 CD34/kg cell dose was collected in a single apheresis. The median CD34/kg cell dose collected for the 14 heavily pre-treated patients was 5.7 x 106/kg (2.32–6.48 x 106/kg). There were no serious AE's related to the use of AMD3100. Transient GI toxicity (mostly diarrhea) occurred in 10 of 20 patients shortly after the injections of AMD3100, but only 3 required therapy. Engraftment data is available for the first 12 patients treated. Time to ANC >500/μl and platelets > 20,000/μl was 9 (range 8–10) and 12 (range 9–19) days respectively. This novel combination of AMD3100 and G-CSF appears to be effective in mobilizing large numbers of CD34+ cells, even in patients considered to be heavily pre-treated, and is an effective alternative to chemotherapy/cytokine mobilization. Compared to studies of G-CSF alone, this combination may reduce the number of apheresis procedures needed to collect an adequate graft for rapid hematopoietic engraftment. The study is ongoing with accrual to date of 40 patients.