A phase 1/2 study of chemosensitization with plerixafor plus G-CSF in relapsed or refractory acute myeloid leukemia

摘要

The interaction of acute myeloid leukemia (AML) blasts with the bone marrow (BM) microenvironment provides potent protection against both spontaneous apoptosis and chemotherapy. 1 Similar to normal hematopoietic stem cells (HSCs), AML blasts express many of the same adhesion molecules such as CXCR4, VLA-4, VLA-5 and CD44, which allow them to interact with the marrow microenvironment. We and others have demonstrated in murine models that CXCR4 inhibitors can mobilize AML cells from the BM into the peripheral blood and enhance the anti-leukemic effects of chemotherapy. 2 , 3 We have also demonstrated in a previous phase 1/2 study that plerixafor, a small molecule inhibitor of CXCR4, can be safely combined with chemotherapy in patients with relapsed or refractory AML with encouraging response rates. 4 Mobilization of HSCs by granulocyte-colony stimulating factor (G-CSF) occurs through downregulation of mRNA and protein levels of CXCL12, the ligand for CXCR4. 5 For mobilization of autologous HSCs, G-CSF acts synergistically when combined with plerixafor and mobilizes higher numbers of CD34 + cells compared with either agent alone. 6 , 7 In AML, ‘priming’ with G-CSF concurrent with chemotherapy may result in superior outcomes for patients receiving induction therapy for AML. 8 We hypothesized that disruption of the interaction between leukemic blasts with the marrow microenvironment using G-CSF in combination with plerixafor would effectively mobilize and sensitize AML blasts to chemotherapy.