title: Establishment of early donor engraftment after reduced-intensity allogeneic hematopoietic stem cell transplantation to potentiate the graft-versus-lymphoma effect against refractory lymphomas.
abstract: Reduced-intensity allogeneic hematopoietic stem cell transplantation (alloHSCT), which typically results in mixed chimerism initially after transplantation, has had limited efficacy in chemotherapy-refractory lymphomas. We hypothesized that the rapid establishment of complete donor chimerism would potentiate a graft-versus-lymphoma effect. Fifteen patients with chemotherapy-refractory lymphoma initially received induction with a conventional chemotherapy regimen (etoposide, prednisone, vincristine, cyclophosphamide, adriamycin, fludarabine [EPOCH-F]) to deplete host T cells and provide disease control prior to alloHSCT. Patients then received conditioning with fludarabine and cyclophosphamide followed by alloHSCT from HLA-matched siblings. Graft-versus-host disease prophylaxis consisted of cyclosporine alone. EPOCH-F resulted in 73% of patients having partial responses or stable disease. EPOCH-F depleted host CD4(+) T cells from a median of 235 cells/microL to 56 cells/microL. Fourteen patients underwent alloHSCT, and all had >95% donor engraftment by day 14 after transplantation. The incidence of Grade II to III acute graft-versus-host disease was 71%. There were two therapy-related deaths. There were 8 partial responses and 3 complete responses (CRs) at day 28. Five additional CRs were observed at day 100 without withdrawal of cyclosporine or donor lymphocyte infusion. The rate of CRs for all 15 patients was 60%. The 1-year progression-free survival rate from time of study entry is 67% with only 1 relapse among 9 CRs. At a median potential follow-up of 28 months, the overall survival rate is 53%. These data demonstrate that a potent and durable graft-versus-lymphoma effect can occur against chemotherapy-refractory lymphomas and suggest that this effect may be associated with rapid, complete donor chimerism after reduced-intensity alloHSCT.
authors.affiliation: Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. mbishop@mail.nih.gov
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bishop
authors.forename: Jeannie Whit-Shan
authors.initials: JW
authors.lastname: Hou
authors.forename: Wyndham H
authors.initials: WH
authors.lastname: Wilson
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Jeanne
authors.initials: J
authors.lastname: Odom
authors.forename: Kathleen
authors.initials: K
authors.lastname: Castro
authors.forename: Claude
authors.initials: C
authors.lastname: Kasten-Sportes
authors.forename: Juan
authors.initials: J
authors.lastname: Gea-Banacloche
authors.forename: Donna
authors.initials: D
authors.lastname: Marchigiani
authors.forename: Ronald
authors.initials: R
authors.lastname: Gress
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Fowler
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000633:toxicity; D004334:Drug Administration Schedule; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000517:prevention & control; D020350:Graft vs Tumor Effect; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D006801:Humans; D008223:Lymphoma / Q000150:complications / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D012074:Remission Induction / Q000379:methods; D016879:Salvage Therapy; D016019:Survival Analysis; D013997:Time Factors; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods; D014184:Transplantation, Homologous; D016896:Treatment Outcome