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

The interaction of acute myeloid leukemia (AML) blasts with the bone marrow (BM) microenvironment provides potent protection against both spontaneous apoptosis and chemotherapy. 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. 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. Mobilization of HSCs by granulocyte-colony stimulating factor (G-CSF) occurs through downregulation of mRNA and protein levels of CXCL12, the ligand for CXCR4. 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. In AML, ‘priming’ with G-CSF concurrent with chemotherapy may result in superior outcomes for patients receiving induction therapy for AML. 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. In this phase 1/2 study (ClinicalTrials.gov NCT00906945), we evaluated the combination of G-CSF and plerixafor in conjunction with mitoxantrone, etoposide and cytarabine (MEC). Eligible participants were adults, age 18–70 years old, with relapsed or refractory AML. Subjects with a peripheral blood blast count of ⩾ 20 × 10/mm, acute promyelocytic leukemia, active central nervous system leukemia or who had been previously treated with MEC chemotherapy were excluded from the study. The primary endpoint in phase I was to determine the maximum tolerated dose and in phase II was to determine the complete response rate (CR+CRi) of plerixafor plus G-CSF in combination with MEC in patients with relapsed or refractory AML. The phase I was performed using a standard 3+3 design escalating to a maximum plerixafor dose of 0.75 mg/kg/day. For the phase II, a bivariate design was used in two stages to allow an interim analysis of toxicity and response rates. Treatment consisted of G-CSF 10 mcg/kg by subcutaneous injection daily on days 1–8. Plerixafor was administered intravenously (IV) on days 3–8. Chemotherapy consisting of mitoxantrone 8 mg/m/day IV, etoposide 100 mg/m/day IV and cytarabine 1000 mg/m/day (MEC) was administered on days 4–8, ~ 4 h after administration of plerixafor. Thirty-five patients with a median age of 56 years (range 29–70) were enrolled and treated on this study. The majority received treatment for first relapse (n= 21, 60%) with 10 patients (29%) having had a prior allogeneic hematopoietic cell transplantation (Table 1). In the phase I, plerixafor was successfully escalated from 0.24 to 0.75 mg/kg/day in five dose cohorts. The plerixafor 0.75 mg/kg/day dose was brought forward in the phase II expansion with a total of 20 patients treated in the first stage of the phase II. After an interim analysis, we observed that 6 out of 20 patients treated at the phase II dose achieved a CR/CRi (30%), which is less than the 7 out of 20 responses (35%) indicated in the study design for proceeding with the second stage of the phase II. As a result, the study was terminated for futility. With a median follow-up of 34.6 months, the median overall survival for all subjects was 7.6 months with a 1-year overall survival of 37% (95% confidence interval: 21.2–53). The median time to neutrophil recovery (ANC⩾ 1000/mm) was 40 days (range 23–62) from the start of treatment (36 days from MEC). The median time to platelet recovery (platelets ⩾ 100 K/mm) was 32 days (range 30–62). Adverse events were typical of those observed for patients with relapsed or refractory AML with the most common non-hematologic adverse events of nausea (69%), vomiting (37%), febrile neutropenia (57%), headache (40%), fatigue (34%), fever (29%) and electrolyte abnormalities (hypocalcemia 37%, hypokalemia 31%) (Supplementary Table S1).