title: Toxicity of high-dose sequential chemotherapy and purged autologous hematopoietic cell transplantation precludes its use in refractory/recurrent non-Hodgkin's lymphoma.
abstract: We conducted a pilot study in 20 patients with high-risk or recurrent/refractory non-Hodgkin's lymphoma (NHL) using high-dose sequential chemotherapy (HDSC) and autologous hematopoietic cell transplantation (AHCT). After cytoreduction with standard salvage therapy, HDSC/AHCT was administered in 4 phases at 2- to 4-week intervals. Phase 1 consisted of cyclophosphamide 7 g/m2 followed by granulocyte colony-stimulating factor (G-CSF) at 10 microg/kg per day and leukapheresis upon recovery from white blood cell nadir. The hematopoietic cell product was enriched by Percoll gradient separation and purged with a B-cell or T-cell monoclonal antibody panel and complement. Phase 2 consisted of methotrexate 8 g/m2 with leucovorin rescue and vincristine 1.4 mg/m2. Phase 3 was etoposide 2 g/m2 with G-CSF 5 microg/kg per day. In phase 4, the preparative regimen of mitoxantrone 60 mg/m2 and melphalan 180 mg/m2 was administered followed by AHCT. The NHL histologies were diffuse large cell, follicular/diffuse mixed, small noncleaved cell, T-cell-rich B-cell, lymphoblastic, and peripheral T cell. The remission status was first partial remission (PR1; n = 1) or beyond first complete remission (post-CR1; n = 19). Of the 20 patients enrolled, 11 proceeded through all 4 phases. Nine were removed from the study after the first or second phase because of progressive disease (n = 5), poor hematopoietic cell mobilization (n = 1), excessive toxicity (n = 2), and chronic active hepatitis C (n = 1). Treatment-related toxicities in the remaining 11 transplant recipients were cardiomyopathy, hemorrhagic cystitis, persistent cytopenias, acute renal failure, abnormal liver function test results, and infectious complications. There were no treatment-related deaths. Eight of the 11 transplant recipients were alive, 6 without disease, at a median follow-up of 2.7 years. The estimated median 2-year event-free survival was 55%, and overall survival was 70%. We conclude that HDSC/AHCT in refractory/recurrent NHL is associated with considerable acute and chronic toxicities. Given the toxicity profile, efficacy data were not sufficiently promising to warrant further study.
authors.affiliation: Division of Bone Marrow Transplantation, Stanford University, California 94305, USA. laura.johnston@stanford.edu
authors.forename: L J
authors.initials: LJ
authors.lastname: Johnston
authors.forename: K E
authors.initials: KE
authors.lastname: Stockerl-Goldstein
authors.forename: W W
authors.initials: WW
authors.lastname: Hu
authors.forename: R S
authors.initials: RS
authors.lastname: Negrin
authors.forename: R T
authors.initials: RT
authors.lastname: Hoppe
authors.forename: K G
authors.initials: KG
authors.lastname: Blume
authors.forename: S J
authors.initials: SJ
authors.lastname: Horning
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D001855:Bone Marrow Diseases / Q000139:chemically induced; D016465:Bone Marrow Purging; D009202:Cardiomyopathies / Q000139:chemically induced; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D003556:Cystitis / Q000139:chemically induced; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D019650:Hematopoietic Stem Cell Mobilization / Q000009:adverse effects*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007239:Infections; D002955:Leucovorin / Q000008:administration & dosage; D015993:Life Tables; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000401:mortality / Q000628:therapy; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000009:adverse effects; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage / Q000009:adverse effects; D010865:Pilot Projects; D016879:Salvage Therapy; D016019:Survival Analysis; D015996:Survival Rate; D019172:Transplantation Conditioning / Q000009:adverse effects*; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D014750:Vincristine; D005047:Etoposide; D003520:Cyclophosphamide; D008942:Mitoxantrone; D008558:Melphalan; D002955:Leucovorin; D008727:Methotrexate