A Pilot Study Evaluating the Safety and Efficacy of AMD3100 for the Mobilization and Transplantation of HLA-Matched Sibling Donor Hematopoietic Stem Cells in Patients with Advanced Hematological Malignancies.

Abstract

Cytokine mobilized peripheral blood (MPB) has become the preferred allograft source for patients with advanced hematological malignancies. Procurement of MPB currently requires from 5 to 6 days of granulocyte colony stimulating factor (G-CSF) administration and is associated with some donor morbidity and high cost. Recent studies suggest G-CSF induces mobilization by indirectly targeting the interaction between the chemokine stromal derived factor 1 (SDF-1) and its receptor CXCR-4. Here we report preliminary results using a direct antagonist of the SDF-1/CXCR-4 interaction, AMD3100, as a single agent to procure MPB from allogeneic donors. Two HLA-identical siblings, both males aged 55 and 58, received one or two doses of AMD3100 at 240mcg/kg followed 4 hours later by leukapheresis (LP). After successful collection and a one week washout period, the same donors were re-mobilized using G-CSF at 10mcg/kg/day followed by LP commencing day 5. The target CD34+ cell dose following each agent was >2.0x10e6/kg recipient weight. The results of the mobilizations and allograft composition are presented in the table.Results of MobilizationAgentAMD3100G-CSFDonor 1Donor 2Donor 1Donor 2Days of Drug administration2265# LP Procedures2121Peak fold ↑ CD34 count in PB761725CD34 dose (x10e6/kg)2.62.12.95.7CD3 dose (x10e8/kg)4.91.51.31.3CD4 dose (x10e8/kg)3.11.00.90.9CD8 dose (x10e8/kg)1.70.41.00.4CD56 dose (x10e7/kg)3.42.12.21.8Following AMD3100, donor 1 did not experience any drug related toxicity and donor 2 developed only grade 1 abdominal bloating. Both donors experienced grade 2 bone pain during G-CSF mobilization. The AMD3100 mobilized cells from donor 1 were transplanted into a 51 year old woman with AML following conditioning with cyclophosphamide (120mg/kg) and total body irradiation (single dose at 550cGy). Single agent cyclosporine was used for GVHD prophylaxis. She engrafted neutrophils >500/ul promptly on day +11 and platelets > 20,000/ul on day +14. A bone marrow biopsy performed on day +30 revealed an overall cellularity of 50% with normal trilineage hematopoiesis and full donor chimerism. By day 30, the peripheral blood CD3 count had reached 531/ul, CD4 count 305/ul, and CD8 count 211/ul. The CD4/8 ratio was 1.4. She is currently being followed as an outpatient and by day +39 is without evidence of GVHD. The allograft from the second donor was not given as the recipient's disease progressed.This is the first demonstration that a chemokine antagonist can induce the rapid mobilization of a functionally competent hematopoietic allograft without causing significant toxicity. Accrual is ongoing and additional donor/recipient pairs will be presented.