A Phase I/II Trial of Plerixafor/G-CSF Combined with IV Bu/Flu Conditioning Regimen In AML/MDS Patients Undergoing Allogenic Stem Cell Transplantation

Abstract 2358

Allogeneic stem cell transplantation (alloSCT) is an effective treatment for pts with acute myeloid leukemia (AML) in first remission. However, only 10–20% of pts with relapsed disease achieve a durable remission. Microenvironment/leukemia interactions play a major role in chemoresistance of leukemic stem cells residing in the bone marrow niches. In pre-clinical in vivo leukemia models, inhibition of chemokine receptor CXCR4 results in mobilization of leukemic cells into circulation and sensitization to chemotherapy. We hypothesized that mobilization of leukemic stem cells by CXCR4 inhibition and G-CSF will result in improved anti-leukemia activity of a standard preparative regimen followed by alloSCT. In this Phase I/II study, G-CSF is administered at a standard dose beginning on day -9 daily for 6 days, and the CXCR4 inhibitor plerixafor (Mozobil^®) from day -7 at one of the 4 dose levels 0 (control), 0.08, 0.16, or 0.24 mg/kg, 8 hours prior of each four daily doses of a standard preparative regimen (Fludarabine, 40mg/m2 and IV Busulfan, 130mg/m2, days -6 through -3).

Twenty seven pts have been enrolled in the study to date with a median age of 48 yrs (range 25–65). Baseline characteristics include 13 pts (48%) with de novo AML, 6 (22%) with secondary AML, 5 with MDS and 3 with CML. Among the 24 AML/MDS pts, 14 (58%) had intermediate and 10 (42%) poor risk cytogenetics. Twelve pts (50%) had primary refractory AML, 5 were in 1^st or 2^nd relapse, 2 were untreated, 3 were in CR1 and 2 in CR2. The source of stem cells was sibling donor in 16 and unrelated donor in 11. After phase I plerixafor dose escalation in 16 pts, 11 pts received 0.24 mg/kg in Phase II. Common grade ≥ 3 adverse events which consisted primarily of neutropenic fever, infections, or rash were seen in 24/27 (89%) pts. There were no toxicities ascribed to the G-CSF/plerixafor component of the regimen. No evidence of significant delays in neutrophil (ANC >500/mm³, median 12.5d, range 10–19) or platelet recovery (plt >20k/mm³, median 12d, range 9–74d) were observed. Grade I-II GVHD was seen in 10/27 pts (37%), with no occurrences of Grade III-IV GVHD. Of the 19 pts with active disease at study entry, 18 achieved a CR. Treatment failure was due to persistent disease in 1 pt (4%), relapsed disease in 10 pts (37%) and early death due to complications from intracranial hemorrhage in 1 pt (4%). Median progression-free survival (PFS) for all pts was 26.6 wks (95%CI: 18.1–33.9 wks) and 15.7 wks (95% CI: 12.1–26.6 wks) in relapsed pts. Median follow-up for all study pts was 19.14 wks (range: 0.7–54.6 wks).

Correlative studies analyzed from 16 pts enrolled in the Phase I portion of the trial demonstrate that G-CSF/plerixafor mobilizes CD34⁺ cells, with the mean fold increase of 5.9-fold at 0.08 mg/kg plerixafor; at 0.16 mg/kg, 13-fold; and at 0.24 mg/kg, 14.2-fold. Based on fitted longitudinal linear mixed models, G-CSF had a significant effect on cell mobilization over time (WBC and CD34⁺). In contrast, plerixafor at the doses of 0.16 and 0.24 mg/kg was significantly associated with increased cellular CXCR4 expression levels and with mobilization of CXCR4⁺ cells over time (p<0.02). To determine relative proportion of mobilization of leukemic and non-leukemic cells, we performed FISH analysis on peripheral blood samples from pts with informative cytogenetic abnormalities (n=12). Both, FISH+ and FISH- cell counts increased from day -8 to day -6 and remained relatively stable or decreased thereafter (between day -6 and day -3), with the initial increase much larger for the plerixafor dose level 0.16 mg/kg (mean fold increase FISH+, 24.3; FISH-, 10.3). Over time, the relative increase of FISH+ cells was significantly higher than that of FISH- cells, indicating preferential mobilization of cytogenetically abnormal leukemic over normal cells (p=0.005).

In summary, G-CSF/plerixafor is safe in combination with the established IV busulfan/fludarabine preparative regimen for alloSCT in pts with advanced disease. Our data indicate preferential mobilization of clonal leukemic over normal cells. The objective of the ongoing Phase II study is to determine if the combination of G-CSF/plerixafor with busulfan/fludarabine improves PFS compared to historical controls receiving busulfan/fludarabine alone. We hypothesize that interventions disrupting stroma-leukemia interactions may enhance chemosensitivity and therefore the therapeutic efficacy in hematological malignancies.