Leukemia Cell Mobilization with Plerixafor Plus G-CSF with Busulfan/Fludarabine and Allogeneic Hematopoietic Cell Transplantation in Patients with AML/MDS Is Associated with Decreased Complete Chimerism and GvHD, and Increased Risk of Relapse

Abstract

AbstractAbstract ▪360▪This icon denotes a clinically relevant abstract Background:The goal of preparative regimen in allogeneic stem cell transplant (allo-SCT) is to eradicate leukemia cells. Relapse remains the major cause of treatment failure in patients receiving allo-SCT for acute myeloid leukemia (AML) and myelodysplasia (MDS). There is accumulating evidence that specific niche interactions between the bone marrow stroma and leukemic cells provide protection from cytotoxic chemotherapy. We hypothesized that disruption of those stromal-leukemia interactions using a CXCR4 inhibitor, plerixafor, in combination with granulocyte-colony stimulating factor (G-CSF), may promote release of leukemic cells from the niche and improve progression-free survival post transplant. Patients and Methods:In a phase 1/2 investigation, we treated 41 AML/MDS patients (34 AML and 7 MDS) with a median age of 55 years (range, 31–65 years) with plerixafor (doses of 0, 80, 160 or 240 mcg/kg daily for 4 days starting on day -7) plus G-CSF (10 mcg/kg daily for 6 days starting on day -9) along with the busulfan/fludarabine (Bu/Flu) conditioning regimen (fixed-dose Bu 130mg/m2 IV daily on days -6 to -3 plus Flu 40mg/m2 IV daily on days -6 to -3). Graft-versus-host disease (GvHD) prophylaxis consisted of tacrolimus plus mini-methotrexate. Results:In the phase 1 portion, we determined that pre-treatment with plerixafor plus fixed dose G-CSF is safe when used with the Bu/Flu conditioning regimen. There were no dose limiting toxicities and the highest dose of plerixafor used in the phase 1 study (240 mcg/kg) was selected for the phase 2 extension. The treatment was successful at preferentially mobilizing leukemic cells, as measured by fluorescent in situ hybridization (FISH), with a median fold increase of 22.5 (range, 2.3–73.8) for FISH-positive cells and 6.7 (range, 1.5–19.1) for FISH-negative cells (difference p-value=0.005). This mobilization effect has not been observed when plerixafor was used alone, without G-CSF, in the treatment of AML.1 The plerixafor plus G-CSF combination increased circulating WBCs and CD34+ cells (for 240mcg/kg dose, median fold increase of 6.3 and 36.8 respectively at day -6), as well as CXCR4+ cells. We found that the increase in circulating blasts and CD34+ cells positively correlated with baseline percentage of bone marrow blasts and peripheral blood WBC/blast count. The clinical effects were examined in patients receiving first transplants for AML/MDS (n=39), and outcomes were compared to historical data from 483 patients receiving Bu/Flu alone prior to allo-SCT. There was no difference in time to engraftment between the two groups. Significantly fewer patients in this study group had complete chimerism at day 30 (28%) when compared to historical data (55%, p-value=0.002). The largest difference was seen in lymphoid chimerism, with <80% donor-derived lymphoid cells at day 30 in 56% in the study group vs. 23% in historical data (p-value=0.001). Median follow-up among surviving patients was 16 months (range 6–28) in the study group and 54 months (range 5–126) in the historical dataset. There was a lower frequency of grade 3–4 acute GvHD in the study group vs. historical data (0% vs. 7%, p-value=0.06), and the rate of extensive chronic GvHD was also lower in the study group (HR at 1 year=0.3, p-value=0.06). Despite the intended biological effect of mobilizing and then eliminating leukemia cells, the cumulative incidence of disease progression for patients transplanted in first remission (CR1) was 47% in the study group vs. 25% in the historical comparison (p-value=0.03) and 62% vs. 40% for those not in CR1 at the time of transplant (p-value=0.07). Overall survival at 2 years was 48% vs. 67% for study and historical patients in CR1 (p-value=0.2), and 34% vs. 47% for patients not in CR1 (p-value=0.5). Conclusions:In summary, our findings demonstrate that the combination of plerixafor plus G-CSF can be safely added to the Bu/Flu conditioning regimen, and preferentially mobilizes leukemic cells. However, the rate of leukemia relapse was higher in these patients compared to historical data. The etiology of this finding is not yet clear, and may be the result of reduced graft-versus-leukemia effect as evidenced by the reduced lymphoid chimerism and rate of GvHD. Disclosures:Off Label Use: Plerixafor plus G-CSF as a part of conditioning in allogenic transplant for AML/MDS. Champlin:Sanofi/Genzyme: Research Funding; Otsuka: Research Funding.