Early Kinetics of Engraftment Following Reduced-Intensity Stem Cell Transplantation: Fludarabine and Cyclophosphamide Versus Fludarabine and Busulfan.

Introduction

Recently, reduced-intensity conditioning (RIC) regimens have been used in allogeneic stem cell transplantation (SCT) in which conventional myeloablative conditioning regimens are associated with high rates of non-relapse mortality. Most commonly used RIC regimens are fludarabine/total body irradiation, fludarabine/cyclophosphamide (F/C), fludarabine/busulfan (F/B), and fludarabine/melphalan, with increasing myelosuppressive intensity. Although patients receiving an allogeneic peripheral blood stem cell (PBSC) transplant after a preparative regimen of F/C were reported to develop first T-cell donor chimerism and later myeloid donor chimerism, how chimerism kinetics may be different for these regimens is not fully elucidated. We have retrospectively analyzed early kinetics of engraftment following reduced-intensity SCT and compared the results of F/C and F/B.

Patients and methods

Data were collected retrospectively on 30 patients who underwent allogeneic SCT after RIC regimens (F/C, n=13; F/B, n=17) between January 2001 and May 2006. F/C patients underwent conditioning a fludarabine and cyclophosphamide regimen consisting of fludarabine 30mg/m2 intravenously daily (days -7 through -2) and cyclophosphamide 30mg/kg intravenously (day -7, -6). F/B patients underwent a fludarabine and busulfan regimen in which busulfan 1mg/kg orally every 6 hours for 2 days (days -5, -4) was substituted for cyclophosphamide. All patients received GVHD prophylaxis with cyclosporine A (from day -1) and short term methotrexate (days +1, +3, +6). Donor chimerism was performed on days 14 and 28 using quantitative polymerase chain reaction of informative polymorphic short tandem repeat regions.

Results

On day 14, donor chimerism of myeloid cells was 25.8% and 68.1% in patients with F/C and F/B, respectively (p=0.023). On the contrary, donor chimerism of T-cells was 71.4% and 34.3% in patients with F/C and F/B, respectively (p=0.024). Similar results were obtained on day 28. Myeloid donor chimerism was 72.0% and 98.6% (p=0.002), and T-cell donor chimerism was 94.5% and 69.3% (p=0.006) in patients with F/C and F/B, respectively.

Discussion

Engraftment kinetics of allogeneic SCT after RIC regimens depend on the intensity of pretransplant chemotherapy, the intensity of the conditioning regimens, and the graft composition. Unfortunately, our analyses were retrospective, and the majority of stem cell source used in F/C was PBSC in contrast to bone marrow in F/B. However, even with PBSC, T-cell donor chimerism was previously reported to be delayed in F/B conditioning compared to myeloid donor chimerism. Our results clearly demonstrated that chimerism kinetics is strikingly different between F/C and F/B and suggested that not only the intensity but also the impact on chimerism of RIC regimens should not be considered equivalent.