Phase I/II study of bortezomib-beam and autologous hematopoietic stem cell transplantation for relapsed indolent non-hodgkin lymphoma, transformed, or mantle cell Lymphoma

Basem M. William, Mary S. Allen, Fausto R. Loberiza, Robert G Bociek, Philip Jay Bierman, James Olen Armitage, Julie Marie Vose

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13 Citations (Scopus)

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 1.5mg/m2) 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 1.5mg/m2 but it was later decreased to 1mg/m2 because of excessive gastrointestinal toxicity and peripheral neuropathy. The ORR was 95% at 100days and 87% at 1year. For all 38 evaluable patients at 1year, responses were CR 84%, PR 1%, and progressive disease 13%. Progression-free survival (PFS) was 83% (95% CI, 68% to 92%) at 1year, and 32% (15% to 51%) at 5years. Overall survival (OS) was 91% (95% CI, 79% to 96%) at 1year and 67% (50% to 79%) at 5years. 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 5years, respectively (log-rank P=.37). OS was 88% and 50% for the BEAM group versus 96% and 72% for V-BEAM at 1 and 5years, 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.

Original languageEnglish (US)
Pages (from-to)536-542
Number of pages7
JournalBiology of Blood and Marrow Transplantation
Volume20
Issue number4
DOIs
StatePublished - Jan 1 2014

Fingerprint

Mantle-Cell Lymphoma
Carmustine
Hematopoietic Stem Cell Transplantation
Melphalan
Cytarabine
Etoposide
Non-Hodgkin's Lymphoma
Maximum Tolerated Dose
Peripheral Nervous System Diseases
Disease-Free Survival
Bortezomib
Vasovagal Syncope
Orthostatic Hypotension
Follicular Lymphoma
Survival
National Cancer Institute (U.S.)
Ileus
Anorexia
Fever

Keywords

  • Autologous
  • Bortezomib
  • Lymphoma
  • Mantle cell
  • Non-Hodgkin lymphoma
  • Stem cell transplantation

ASJC Scopus subject areas

  • Hematology
  • Transplantation

Cite this

@article{3bf2439576c94a419f122ae05f912a6d,
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 1.5mg/m2) 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 1.5mg/m2 but it was later decreased to 1mg/m2 because of excessive gastrointestinal toxicity and peripheral neuropathy. The ORR was 95{\%} at 100days and 87{\%} at 1year. For all 38 evaluable patients at 1year, responses were CR 84{\%}, PR 1{\%}, and progressive disease 13{\%}. Progression-free survival (PFS) was 83{\%} (95{\%} CI, 68{\%} to 92{\%}) at 1year, and 32{\%} (15{\%} to 51{\%}) at 5years. Overall survival (OS) was 91{\%} (95{\%} CI, 79{\%} to 96{\%}) at 1year and 67{\%} (50{\%} to 79{\%}) at 5years. 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 5years, respectively (log-rank P=.37). OS was 88{\%} and 50{\%} for the BEAM group versus 96{\%} and 72{\%} for V-BEAM at 1 and 5years, 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.",
keywords = "Autologous, Bortezomib, Lymphoma, Mantle cell, Non-Hodgkin lymphoma, Stem cell transplantation",
author = "William, {Basem M.} and Allen, {Mary S.} and Loberiza, {Fausto R.} and Bociek, {Robert G} and Bierman, {Philip Jay} and Armitage, {James Olen} and Vose, {Julie Marie}",
year = "2014",
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doi = "10.1016/j.bbmt.2014.01.004",
language = "English (US)",
volume = "20",
pages = "536--542",
journal = "Biology of Blood and Marrow Transplantation",
issn = "1083-8791",
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TY - JOUR

T1 - Phase I/II study of bortezomib-beam and autologous hematopoietic stem cell transplantation for relapsed indolent non-hodgkin lymphoma, transformed, or mantle cell Lymphoma

AU - William, Basem M.

AU - Allen, Mary S.

AU - Loberiza, Fausto R.

AU - Bociek, Robert G

AU - Bierman, Philip Jay

AU - Armitage, James Olen

AU - Vose, Julie Marie

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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 1.5mg/m2) 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 1.5mg/m2 but it was later decreased to 1mg/m2 because of excessive gastrointestinal toxicity and peripheral neuropathy. The ORR was 95% at 100days and 87% at 1year. For all 38 evaluable patients at 1year, responses were CR 84%, PR 1%, and progressive disease 13%. Progression-free survival (PFS) was 83% (95% CI, 68% to 92%) at 1year, and 32% (15% to 51%) at 5years. Overall survival (OS) was 91% (95% CI, 79% to 96%) at 1year and 67% (50% to 79%) at 5years. 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 5years, respectively (log-rank P=.37). OS was 88% and 50% for the BEAM group versus 96% and 72% for V-BEAM at 1 and 5years, 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.

AB - 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 1.5mg/m2) 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 1.5mg/m2 but it was later decreased to 1mg/m2 because of excessive gastrointestinal toxicity and peripheral neuropathy. The ORR was 95% at 100days and 87% at 1year. For all 38 evaluable patients at 1year, responses were CR 84%, PR 1%, and progressive disease 13%. Progression-free survival (PFS) was 83% (95% CI, 68% to 92%) at 1year, and 32% (15% to 51%) at 5years. Overall survival (OS) was 91% (95% CI, 79% to 96%) at 1year and 67% (50% to 79%) at 5years. 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 5years, respectively (log-rank P=.37). OS was 88% and 50% for the BEAM group versus 96% and 72% for V-BEAM at 1 and 5years, 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.

KW - Autologous

KW - Bortezomib

KW - Lymphoma

KW - Mantle cell

KW - Non-Hodgkin lymphoma

KW - Stem cell transplantation

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DO - 10.1016/j.bbmt.2014.01.004

M3 - Article

VL - 20

SP - 536

EP - 542

JO - Biology of Blood and Marrow Transplantation

JF - Biology of Blood and Marrow Transplantation

SN - 1083-8791

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