title: Phase I/II study of bortezomib-BEAM and autologous hematopoietic stem cell transplantation for relapsed indolent non-Hodgkin lymphoma, transformed, or mantle cell lymphoma.
abstract: A phase I/II trial was designed to evaluate the safety and efficacy of adding bortezomib to standard BEAM (BCNU, etoposide, cytarabine, melphalan) and autologous hematopoietic stem cell transplantation (ASCT). Eligible patients had relapsed/refractory indolent or transformed non-Hodgkin lymphoma or mantle cell lymphoma (MCL) that was relapsed/refractory or in first partial (PR) or complete remission (CR). Patients received bortezomib on days -11, -8, -5, and -2 before ASCT. Phase I had 4 dose cohorts (.8, 1, 1.3, and 1.5 mg/m(2)) and 3 patients were accrued to each. Any nonhematological ASCT-related toxicity >2 on the Bearman scale occurring between day -11 and engraftment defined the maximum tolerated dose (MTD). After the MTD has been reached, another 20 patients were enrolled at this dose to determine a preliminary overall response rate (ORR). Patients who were in CR or PR at day +100 were considered responders. The study enrolled 42 patients through August 14, 2009. The median age was 58 (range, 34 to 73) years, with 33 males and 9 females. The most common diagnoses were MCL (23 patients) and follicular lymphoma (7 patients). The median number of prior therapies was 1 (range, 0 to 6). The median follow-up was 4.88 (range, 1.07 to 6.98) years. Thirteen patients were treated in phase I and 29 patients were treated in phase II. The MTD was initially determined to be 1.5 mg/m(2) but it was later decreased to 1 mg/m(2) because of excessive gastrointestinal toxicity and peripheral neuropathy. The ORR was 95% at 100 days and 87% at 1 year. For all 38 evaluable patients at 1 year, responses were CR 84%, PR 1%, and progressive disease 13%. Progression-free survival (PFS) was 83% (95% CI, 68% to 92%) at 1 year, and 32% (15% to 51%) at 5 years. Overall survival (OS) was 91% (95% CI, 79% to 96%) at 1 year and 67% (50% to 79%) at 5 years. The most common National Cancer Institute grade 3 toxicities were neutropenic fever (59%), anorexia (21%), peripheral neuropathy (19%), orthostatic hypotension/vasovagal syncope (16%), and 1 patient failed to engraft. Compared with 26 MCL in CR1 historic controls treated with BEAM and ASCT, PFS was 85% and 43% for the BEAM group versus 87% and 57% for those who received bortezomib in addition to standard BEAM (V-BEAM) at 1 and 5 years, respectively (log-rank P = .37). OS was 88% and 50% for the BEAM group versus 96% and 72% for V-BEAM at 1 and 5 years, respectively (log-rank P = .78). In conclusion, V-BEAM and ASCT is feasible. The toxicities were manageable and we did not observe any treatment-related mortalities; however, we did observe an excess of autonomic dysfunction and ileus, which is concerning for overlapping toxicity with BEAM conditioning. Determining relative efficacy of V-BEAM compared to BEAM would require a randomized trial.
authors.affiliation: Division of Oncology/Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska. Electronic address: bmw93@case.edu.
authors.forename: Basem M
authors.initials: BM
authors.lastname: William
authors.affiliation: Division of Oncology/Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Mary S
authors.initials: MS
authors.lastname: Allen
authors.affiliation: Division of Oncology/Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Fausto R
authors.initials: FR
authors.lastname: Loberiza
authors.affiliation: Division of Oncology/Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Robert Gregory
authors.initials: RG
authors.lastname: Bociek
authors.affiliation: Division of Oncology/Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Bierman
authors.affiliation: Division of Oncology/Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: James O
authors.initials: JO
authors.lastname: Armitage
authors.affiliation: Division of Oncology/Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Vose
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D000069286:Bortezomib; D002330:Carmustine / Q000008:administration & dosage / Q000009:adverse effects; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008558:Melphalan / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects; D012008:Recurrence; D012074:Remission Induction; D016019:Survival Analysis; D014182:Transplantation, Autologous
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D003561:Cytarabine; D000069286:Bortezomib; D005047:Etoposide; D008558:Melphalan; D002330:Carmustine
keywords: Autologous; Bortezomib; Lymphoma; Mantle cell; Non-Hodgkin lymphoma; Stem cell transplantation