title: Vorinostat Combined with High-Dose Gemcitabine, Busulfan, and Melphalan with Autologous Stem Cell Transplantation in Patients with Refractory Lymphomas.
abstract: More active high-dose regimens are needed for refractory/poor-risk relapsed lymphomas. We previously developed a regimen of infusional gemcitabine/busulfan/melphalan, exploiting the synergistic interaction. Its encouraging activity in refractory lymphomas led us to further enhance its use as a platform for epigenetic modulation. We previously observed increased cytotoxicity in refractory lymphoma cell lines when the histone deacetylase inhibitor vorinostat was added to gemcitabine/busulfan/melphalan, which prompted us to clinically study this four-drug combination. Patients ages 12 to 65 with refractory diffuse large B cell lymphoma (DLCL), Hodgkin (HL), or T lymphoma were eligible. Vorinostat was given at 200 mg/day to 1000 mg/day (days -8 to -3). Gemcitabine was infused continuously at 10 mg/m(2)/minute over 4.5 hours (days -8 and -3). Busulfan dosing targeted 4000 μM-minute/day (days -8 to -5). Melphalan was infused at 60 mg/m(2)/day (days -3 and -2). Patients with CD20(+) tumors received rituximab (375 mg/m(2), days +1 and +8). We enrolled 78 patients: 52 DLCL, 20 HL, and 6 T lymphoma; median age 44 years (range, 15 to 65); median 3 prior chemotherapy lines (range, 2 to 7); and 48% of patients had positron emission tomography-positive tumors at high-dose chemotherapy (29% unresponsive). The vorinostat dose was safely escalated up to 1000 mg/day, with no treatment-related deaths. Toxicities included mucositis and dermatitis. Neutrophils and platelets engrafted promptly. At median follow-up of 25 (range, 16 to 41) months, event-free and overall survival were 61.5% and 73%, respectively (DLCL) and 45% and 80%, respectively (HL). In conclusion, vorinostat/gemcitabine/busulfan/melphalan is safe and highly active in refractory/poor-risk relapsed lymphomas, warranting further evaluation. This trial was registered at ClinicalTrials.gov (NCI-2011-02891).
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: ynieto@mdanderson.org.
authors.forename: Yago
authors.initials: Y
authors.lastname: Nieto
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Benigno C
authors.initials: BC
authors.lastname: Valdez
authors.affiliation: Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Thall
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sairah
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Roy B
authors.initials: RB
authors.lastname: Jones
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chitra
authors.initials: C
authors.lastname: Hosing
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Uday
authors.initials: U
authors.lastname: Popat
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Shpall
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Muzaffar
authors.initials: M
authors.lastname: Qazilbash
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Alison
authors.initials: A
authors.lastname: Gulbis
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Paolo
authors.initials: P
authors.lastname: Anderlini
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Amin
authors.initials: A
authors.lastname: Alousi
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Nina
authors.initials: N
authors.lastname: Shah
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Qaiser
authors.initials: Q
authors.lastname: Bashir
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Oki
authors.affiliation: Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Frederick
authors.initials: F
authors.lastname: Hagemeister
authors.affiliation: Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michelle
authors.initials: M
authors.lastname: Fanale
authors.affiliation: Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Bouthaina
authors.initials: B
authors.lastname: Dabaja
authors.affiliation: Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Pinnix
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Richard
authors.initials: R
authors.lastname: Champlin
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Borje S
authors.initials: BS
authors.lastname: Andersson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002066:Busulfan / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006689:Hodgkin Disease / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D008558:Melphalan / Q000627:therapeutic use; D008875:Middle Aged; D012008:Recurrence; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000379:methods*; D014182:Transplantation, Autologous; D000077337:Vorinostat; D000093542:Gemcitabine
chemical_list: D006877:Hydroxamic Acids; D003841:Deoxycytidine; D000077337:Vorinostat; D002066:Busulfan; D008558:Melphalan; D000093542:Gemcitabine
keywords: Autologous stem-cell transplantation; High-dose chemotherapy; Lymphoma; Phase 1 trial; Vorinostat