Abstract
Abstract Reduced-intensity conditioning regimens prior to allogeneic hematopoietic stem cell transplantation (RIC allo-HSCT) contain cytotoxic agents to create marrow space for donor cells and rely on graft-vs-leukemia effect for curative potential. Pentostatin is in the same class of chemotherapeutics as the purine analog fludarabine, which is commonly used in RIC allo-HSCT. However, pentostatin has a unique mechanism of action that targets adenosine deaminase and may allow for selective targeting of lymphocytes. We hypothesize that pentostatin can be used as an alternative to fludarabine in an MHC-disparate murine setting (stringent model). We compared the immune effects of pentostatin (1 mg/kg/d) and fludarabine (100 mg/kg/d) alone to each in combination therapy with cyclophosphamide (50 or 100 mg/kg/d). BALB/c mice were treated with a three-day regimen followed by transplantation of B6 bone marrow. Combination PC or FC were each more effective at depleting and suppressing splenic T cells than either agent alone; however, the PC regimen was synergistic in depleting host CD4+ T cells (p<0.01) and CD8+ T cells (p<0.01), and suppressing their function. Immune depletion was characterized by spleen harvest followed by flow cytometry at different times during treatment, while host immune suppression was evaluated by cytokine content in multiplex bead array (Bio-Rad). Surprisingly, recipients in both cohorts rejected the graft. We then reasoned that the rejection was mediated by host immune reconstitution. Indeed, CD4+ T cells of BALB/c mice rebounded to 22.4% (p<0.0001) of pre-treatment levels 10 days after conditioning with PC, and cohorts treated with FC rebounded to 58.8% (p<0.001) of pre-treatment levels (means of 26.7∗106 cells in HBSS, 6.0 ∗ 106 for P, 15.7∗106 for F, 1.9∗106 for XRT). We successfully developed a more immunodepletive regimen by intensification of cyclophosphamide therapy to 14 days with P or F administered every 3 days. In this model, PC demonstrated approximately a 75-fold decrease in CD4+ cells two weeks after the end of treatment (8.3 × 106 v. 0.12 × 106, p<0.05) and FC a 15-fold decrease (0.53 × 106, p<0.05) compared to controls; granulocytes were preserved in both cases (#Gr1+ cells). The 14-day regimen also allowed for engraftment in both PC and FC, with 93% of PC–treated and 57% of FC-treated cohorts achieving >5% donor chimerism (p<0.0001). In conclusion, pentostatin facilitates engraftment in stringent, fully-MHC disparate model, therefore we posit it can be used as a fludarabine alternative in a reduced-intensity human transplant setting. Citation Information: Clin Cancer Res 2010;16(7 Suppl):B19
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