title: Intensified and high-dose chemotherapy with granulocyte colony-stimulating factor and autologous stem-cell transplantation support as first-line therapy in high-risk diffuse large-cell lymphoma.
abstract: OBJECTIVE
  In our previous study with MACOPB, we identified a high-risk group of patients with a poor 3-year survival rate of 29%. These patients were defined as having at diagnosis advanced-stage disease with high tumor burden (TB) and elevated lactate dehydrogenase (LDH) level or bone marrow (BM) involvement. A novel therapeutic scheme was investigated to improve the outcome of these patients.
  
  
  METHODS
  Fifty patients with high-risk diffuse large-cell lymphoma (DLCL) were enrolled. The therapeutic scheme includes three phases: induction with 8 weeks of MACOPB; intensification with a 3-day course of mitoxantrone 8 mg/m2 plus high-dose cytarabine (HDARA-C) 2 g/m2 every 12 hours plus dexamethasone 4 mg/m2 every 12 hours (MAD protocol) and granulocyte colony-stimulating factor (G-CSF) 5 microg/kg on days 4 to 17 to harvest peripheral-blood progenitor cells (PBPC); consolidation with carmustine (BCNU), etoposide, ARA-C, and melphalan (BEAM) regimen; plus autologous stem-cell transplantation (ASCT) with PBPC, marrow, or both.
  
  
  RESULTS
  Thirty-six patients (72%) achieved a complete response (CR), 11 (22%) showed no response (NR), and three (6%) died of toxicity. Among the 22 PRs or NRs after the induction phase, 56% of patients achieved a CR with subsequent intensified therapy. With a median follow-up duration of 32 months, the overall survival and failure-free survival rates were 56% and 50%, respectively. The disease-free survival rate is 69% at 32 months. Leukapheresis after MAD and G-CSF yielded a median of 32 x 10(6)/kg CD34+ cells and 80 x 10(4)/kg granulocyte-macrophage colony-forming units (CFU-GM). Thirty-nine patients were autografted and 11 did not undergo ASCT: six because of disease progression, four due to toxicity, and one because of patient refusal. The median times to achieve engrafment were 11 days (range, 7 to 19) to a neutrophil count greater than 0.5 x 10(9)/L and 12 days (range, 8 to 60) to a platelet count greater than 50 x 10(9)/L.
  
  
  CONCLUSIONS
  This sequential scheme with intensified and high-dose chemotherapy with ASCT is feasible with moderate toxicity and may improve the outcome in high-risk DLCL.
authors.affiliation: Divisione di Ematologia Azienda Ospedaliera S. Giovanni Battista, Torino, Italy.
authors.forename: U
authors.initials: U
authors.lastname: Vitolo
authors.forename: S
authors.initials: S
authors.lastname: Cortellazzo
authors.forename: A M
authors.initials: AM
authors.lastname: Liberati
authors.forename: R
authors.initials: R
authors.lastname: Freilone
authors.forename: M
authors.initials: M
authors.lastname: Falda
authors.forename: M
authors.initials: M
authors.lastname: Bertini
authors.forename: B
authors.initials: B
authors.lastname: Botto
authors.forename: S
authors.initials: S
authors.lastname: Cinieri
authors.forename: A
authors.initials: A
authors.lastname: Levis
authors.forename: F
authors.initials: F
authors.lastname: Locatelli
authors.forename: E
authors.initials: E
authors.lastname: Lovisone
authors.forename: F
authors.initials: F
authors.lastname: Marmont
authors.forename: M
authors.initials: M
authors.lastname: Pizzuti
authors.forename: A
authors.initials: A
authors.lastname: Rossi
authors.forename: P
authors.initials: P
authors.lastname: Viero
authors.forename: T
authors.initials: T
authors.lastname: Barbui
authors.forename: F
authors.initials: F
authors.lastname: Grignani
authors.forename: L
authors.initials: L
authors.lastname: Resegotti
mesh_terms: D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001761:Bleomycin / Q000008:administration & dosage; D016026:Bone Marrow Transplantation; D002330:Carmustine; D003520:Cyclophosphamide / Q000008:administration & dosage; D003561:Cytarabine / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005047:Etoposide; D005240:Feasibility Studies; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D007937:Leukapheresis; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000628:therapy*; D008297:Male; D008558:Melphalan; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D010865:Pilot Projects; D011241:Prednisone / Q000008:administration & dosage; D012306:Risk; D016019:Survival Analysis; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D000964:Antimetabolites, Antineoplastic; D018931:Antineoplastic Agents, Hormonal; D003561:Cytarabine; D001761:Bleomycin; D016179:Granulocyte Colony-Stimulating Factor; D014750:Vincristine; D005047:Etoposide; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; D008942:Mitoxantrone; D008558:Melphalan; D002955:Leucovorin; D002330:Carmustine; D011241:Prednisone; D008727:Methotrexate