Phase II Clinical Experience with Dose-Adjusted EPOCH-Fludarabine, a Novel Regimen for Targeted Immune Depletion (TID) and Disease Control in Patients with Lymphoid Malignancies Prior to Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation (RIST).

Abstract

Reduced-intensity conditioning is less potently tumoricidal than myeloablative regimens; thus, RIST relies more upon graft-versus-tumor (GVT) effects for disease eradication. However, variation in baseline host immune status contributes to inconsistent donor engraftment and may impede maximal GVT effects after RIST. We hypothesized that targeted immune depletion (TID) with conventional-dose chemotherapy before RIST might facilitate donor engraftment, thereby potentiating GVT effects. Thus, we evaluated dose-adjusted (DA-) EPOCH-F, a novel regimen of etoposide, prednisone, vincristine, cyclophosphamide (Cy), doxorubicin, and fludarabine (Flu), in a phase II manner in 83 pts with lymphoid malignancies undergoing RIST on 3 sequential, prospective clinical trials between 1999 and 2005. Pts received at least 1 and no more than 3 cycles of DA-EPOCH-F, targeting a peripheral blood CD4+ T cell count < 100 cells/μL. Pts achieving this CD4 count after only 1 or 2 cycles then proceeded to Flu/Cy conditioning and RIST from HLA-matched related donors. Pts otherwise proceeded to RIST after 3 cycles or if disease progression occurred during DA-EPOCH-F, regardless of CD4 count. After 2002, pts with CD20+ malignancies (n=28) also received rituximab (R) on day 1 of each DA-EPOCH-F cycle. Pt characteristics: median age 50 yrs; diagnoses Hodgkin lymphoma (14%), DLBCL (28%), other aggressive NHL (37%), follicular NHL (12%), CLL or other indolent NHL (8%); chemosensitive disease in 48%; median 3 prior regimens, prior autologous stem cell transplant in 28%; poor-risk IPI, FLIPI, IPF score, or Rai stage in 36%. Pts received 1 (n=26), 2 (n=20), or 3 (n=37) cycles of DA-EPOCH-F before RIST. Median CD4 count declined from 284 cells/μL at enrollment to 79 cells/μL after DA-EPOCH-F, which similarly depleted CD8+ T cells and B cells. DA-EPOCH-F toxicities were mainly hematologic and transient. Responses to DA-EPOCH-F were CR/CRu (11%), PR (27%), SD (35%), and PD (23%). Response rates differed by histology (P=0.006); DLBCL or other aggressive NHL were less likely to respond. Baseline CD4 counts were higher in DA-EPOCH-F responders than in non-responders (median 374 vs. 181 cells/μL; P=0.003), despite a similar extent of prior therapy. Full donor chimerism was present by day 14 after RIST in 85% of pts; no graft rejection occurred. The absolute lymphocyte count (ALC) after DA-EPOCH-F was more strongly associated with donor chimerism after RIST (P=0.02) than was CD4+ or other lymphocyte subsets. We retrospectively compared immune depletion in DA-EPOCH-F recipients with that observed in 17 previously untreated pts receiving 6 cycles of DA-EPOCH-R for mantle cell NHL. Although pts receiving DA-EPOCH-F before RIST had lower baseline ALC and all lymphocyte subsets except NKT cells, relative depletion of ALC, T and B cells from baseline levels was surprisingly similar with DA-EPOCH-F and DA-EPOCH-R. We conclude that DA-EPOCH-F effectively provides TID and disease control or stability in most pts with lymphoid malignancies prior to RIST. This strategy is associated with rapid conversion to full donor chimerism and may be useful to enhance potential GVT effects after RIST.