Mobilization and Chemosensitization of AML with the CXCR4 Antagonist Plerixafor (AMD3100): A Phase I/II Study of AMD3100+MEC in Patients with Relapsed or Refractory Disease.

The interaction of leukemic blasts with the bone marrow microenvironment is postulated to be an important mediator of chemoresistance in AML. Although a number of receptor/ligand pairs have been implicated, the CXCR4/SDF-1 axis functions as the principal regulator of homing and retention of both normal and malignant hematopoietic cells in the marrow. Plerixafor (AMD3100) is a bicyclam molecule which reversibly blocks CXCR4 binding to SDF-1 and is being developed clinically as a mobilization agent for hematopoietic stem cell transplantation. Preclinical data from our group has demonstrated that in murine models, plerixafor can disrupt the interaction of leukemic cells with the marrow microenvironment and sensitize blasts to the effect of chemotherapy. Based on these data, we have initiated a phase I/II study in patients with relapsed or refractory AML in which plerixafor is administered prior to salvage chemotherapy. Subjects were required to have AML which is

• primary refractory to at least 2 induction regimens,

• in 1^st relapse with an initial remission duration of < 12 months,

• in 1^st relapse having failed ≥ 1 salvage regimens, or

• in 2^nd relapse or higher. Plerixafor is administered by SQ injection followed by a 24 hour observation period to analyze its effects on leukemic cell mobilization.

Then plerixafor is given daily 4 hours prior to chemotherapy consisting of mitoxantrone 8mg/m²/d, etoposide 100 mg/m²/d and cytarabine 1000 mg/m²/d x 5 days. To date, 19 patients have been treated at 3 dose levels of plerixafor: 80, 160 and 240 mcg/kg/day. We find that plerixafor can modestly mobilize leukemic cells (~ 2-fold increase) into the peripheral circulation at a peak of 6–8 hours after administration. FISH studies performed from informative samples demonstrates that this mobilization occurs equally in both non-leukemic and leukemic populations. While CXCR4 expression is increased on the surface of mobilized blasts, no clear relationship has been observed between CXCR4 expression or plerixafor dose and mobilization. At the 80 and 160 mcg/kg dose levels, a complete response (CR+CRi) was observed in 2 of 6 patients (33%). At the plerixafor 240 mcg/kg dose level, a complete response (CR+CRi) was achieved in 6 of 8 evaluable patients (75%) in this historically chemorefractory population. Plerixafor was well tolerated with no evidence of hyperleukocytosis or significant delays in neutrophil recovery (median 30 days, range 24–40). Based on this encouraging evidence of safety and efficacy, expansion of a phase II cohort is ongoing.