Early data indicate that nonmyeloablative (NM) conditioning regimens have limited antitumor activity and result in mixed donor/host chimerism after allogeneic stem cell transplant(alloSCT). We designed a strategy using an immune depleting induction regimen prior to a NM conditioning regimen and alloSCT. Our aim was to develop a strategy that was safe, controlled tumor growth and had host T cell depleting activity. Based on the immune suppression and antitumor effects observed when fludarabine (FAMP) is combined with alkylators, topo II inhibitors or steroids, we developed the induction regimen, EPOCHF (etoposide 50 mg/m2/day, doxorubicin 10 mg/m2/day, & vincristine 0.5 mg/ml/day CIV days 1-3; prednisone 60 mg/m2/day po days 1-4; FAMP 25 mg/mVday IV bolus days 1-3; cyclophosphamide 600 mg/m2/day IV bolus day 4). EPOCH-F was given q21 days for 1 to 3 cycles to reach a targeted CD4 count <50 cells/ul. After EPOCH-F, patients (pts) received conditioning regimen with FC (FAMP 30 mg/m2/day & cyclophosphamide 1200 mg/mV day IV bolus days 1 -4). The schedule of FC was based on synergistic T cell depletion seen with simultaneous administration of these agents in a murine model. Eight pts enrolled had a median age=41 (33-51) yrs and B-cell histologies (NHL=7,CLL=1). Six pts had advanced refractory disease and had received a median of 3 prior regimens. Pts required a median of 2 cycles of EPOCH-F to reach CD4 <50 cells/ul. Median CD4/CD8 counts (cells/ul) decreased from 251(16-1697) and 173 (15-933) to 49 (9-141) and 22(2-309), respectively, after EPOCH-F. FC produced further T cell depletion to a median CD4 of 2.3(0.3-39) and CDS of 0.1 (0.1 -1.4). EPOCH-F was well tolerated with grade 4 thrombocytopenia in 4/17 cycles. Response to EPOCH-F was stable disease(SD)=6 and partial response(PR)=2, and response at day 28 after alloSCT was CR=4,PR=2 and SD=2. Median time to ANO500 was 9 days (8-11). All pts engrafted (>95% donor engraftment by VNTR=7/8 pts on day +14). Complications in the first 28 days included engraftment syndrome (3/8 pts) and acute GVHD (8/8 pts, grade I-III). EPOCH-F provided tumor control while significantly reducing CD4/CD8 counts. In combination with FC, this two-phased immunoablative strategy for NM alloSCT safely achieved tumor reduction in refractory B cell neoplasms and resulted in profound host T cell depletion with rapid complete donor engraftment after alloSCT. An immunoablative strategy with antitumor activity prior to alloSCT merits further investigation in other disease settings.
|Original language||English (US)|
|Issue number||11 PART II|
|State||Published - Dec 1 2000|
ASJC Scopus subject areas
- Cell Biology