Introduction: The success of autologous stem cell transplantation (ASCT) for treating non-Hodgkin’s lymphoma (NHL) is limited by its high relapse rates. To reduce the risk of relapse, additional maintenance therapy can be added post-transplant. In a non-transplant setting at the time of initiation of this study, both bortezomib and vorinostat had been studied alone or in combination for some NHL histology and showed some clinical activity. At our center, this combination therapy post-transplant for multiple myeloma showed acceptable toxicity. Therefore, it seemed reasonable to study this combination therapy post-ASCT for NHL. Methods: NHL patients underwent conditioning for ASCT with rituximab, carmustine, etoposide, cytarabine, melphalan/carmustine, etoposide, cytarabine, melphalan. After recovery from the acute transplant-related toxicity, combination therapy with IV bortezomib and oral vorinostat (BV) was started and was given for a total of 12 (28-day) cycles. Results: Nineteen patients received BV post-ASCT. The most common toxicities were hematologic, gastrointestinal, metabolic, fatigue, and peripheral neuropathy. With a median follow-up of 10.3 years, 11 patients (58%) are alive without disease progression and 12 patients (63%) are alive. Conclusions: BV can be given post-ASCT for NHL and produces excellent disease-free and overall survival rates.

1.
Vose JM, Rizzo DJ, Tao-Wu J, Armitage JO, Bashey A, Burns LJ, et al. Autologous transplantation for diffuse aggressive non-Hodgkin lymphoma in first relapse or second remission. Biol Blood Marrow Transplant. 2004;10(2):116–27.
2.
Cao TM, Horning S, Negrin RS, Hu WW, Johnston LJ, Taylor TL, et al. High-dose therapy and autologous hematopoietic-cell transplantation for follicular lymphoma beyond first remission: the Stanford University experience. Biol Blood Marrow Transplant. 2001;7(5):294–301.
3.
Ganti AK, Bierman PJ, Lynch JC, Bociek RG, Vose JM, Armitage JO. Hematopoietic stem cell transplantation in mantle cell lymphoma. Ann Oncol. 2005;16(4):618–24.
4.
Smith SM, Burns LJ, van Besien K, Lerademacher J, He W, Fenske TS, et al. Hematopoietic cell transplantation for systemic mature T-cell non-Hodgkin lymphoma. J Clin Oncol. 2013;31(25):3100–9.
5.
Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2006;24(30):4867–74.
6.
O’Connor OA, Wright J, Moskowitz C, Muzzy J, MacGregor-Cortelli B, Stubblefield M, et al. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol. 2005;23(4):676–84.
7.
Chen RW, Palmer JM, Tomassetti S, Popplewell LL, Alluin J, Chomchan P, et al. Multi-center phase II trial of bortezomib and rituximab maintenance combination therapy in patients with mantle cell lymphoma after consolidative autologous stem cell transplantation. J Hematol Oncol. 2018;11(1):87.
8.
Kaplan LD, Maurer MJ, Stock W, Bartlett NL, Fulton N, Pettinger A, et al. Bortezomib consolidation or maintenance following immunochemotherapy and autologous stem cell transplantation for mantle cell lymphoma: CALGB/Alliance 50403. Am J Hematol. 2020;95(6):583–93.
9.
Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol. 2012;30(24):2946–55.
10.
Liu X, He CK, Meng X, He L, Li K, Liang Q, et al. Bortezomib-based vs non-bortezomib-based post-transplantation treatment in multiple myeloma patients: a systematic review and meta-analysis of Phase III randomized controlled trials. Onco Targets Ther. 2015;8:1459–69.
11.
Johnstone RW. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov. 2002;1(4):287–99.
12.
Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer. 2001;1(3):194–202.
13.
Skov S, Pedersen MT, Andresen L, Straten PT, Woetmann A, Odum N. Cancer cells become susceptible to natural killer cell killing after exposure to histone deacetylase inhibitors due to glycogen synthase kinase-3-dependent expression of MHC class I-related chain A and B. Cancer Res. 2005;65(23):11136–45.
14.
Leoni F, Zaliani A, Bertolini G, Porro G, Pagani P, Pozzi P, et al. The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines. Proc Natl Acad Sci U S A. 2002;99(5):2995–3000.
15.
Kelly WK, O’Connor OA, Krug LM, Chiao JH, Heaney M, Curley T, et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol. 2005;23(17):3923–31.
16.
Crump M, Coiffier B, Jacobsen ED, Sun L, Ricker JL, Xie H, et al. Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma. Ann Oncol. 2008;19(5):964–9.
17.
Kirschbaum M, Frankel P, Popplewell L, Zain J, Delioukina M, Pullarkat V, et al. Phase II study of vorinostat for treatment of relapsed or refractory indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. J Clin Oncol. 2011;29(9):1198–203.
18.
Watanabe T, Kato H, Kobayashi Y, Yamasaki S, Morita-Hoshi Y, Yokoyama H, et al. Potential efficacy of the oral histone deacetylase inhibitor vorinostat in a phase I trial in follicular and mantle cell lymphoma. Cancer Sci. 2010;101(1):196–200.
19.
Heider U, von Metzler I, Kaiser M, Rosche M, Sterz J, Rotzer S, et al. Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in mantle cell lymphoma. Eur J Haematol. 2008;80(2):133–42.
20.
Hideshima T, Richardson PG, Anderson KC. Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther. 2011;10(11):2034–42.
21.
Dasmahapatra G, Lembersky D, Kramer L, Fisher RI, Friedberg J, Dent P, et al. The pan-HDAC inhibitor vorinostat potentiates the activity of the proteasome inhibitor carfilzomib in human DLBCL cells in vitro and in vivo. Blood. 2010;115(22):4478–87.
22.
Pei XY, Dai Y, Grant S. Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors. Clin Cancer Res. 2004;10(11):3839–52.
23.
Grant S, Dai Y. Histone deacetylase inhibitors and rational combination therapies. Adv Cancer Res. 2012;116:199–237.
24.
Weber DM, Graef T, Hussein M, Sobecks RM, Schiller GJ, Lupinacci L, et al. Phase I trial of vorinostat combined with bortezomib for the treatment of relapsing and/or refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2012;12(5):319–24.
25.
Dimopoulos M, Siegel DS, Lonial S, Qi J, Hajek R, Facon T, et al. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol. 2013;14(11):1129–40.
26.
Siegel DS, Dimopoulos M, Jagannath S, Goldschmidt H, Durrant S, Kaufman JL, et al. Vantage 095: an international, multicenter, open-label study of vorinostat (MK-0683) in combination with bortezomib in patients with relapsed and refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2016;16(6):329–34.e1.
27.
Ogawa Y, Ogura M, Tobinai K, Ando K, Suzuki T, Watanabe T, et al. A phase I study of vorinostat combined with bortezomib in Japanese patients with relapsed or refractory multiple myeloma. Int J Hematol. 2016;103(1):25–33.
28.
Bhatt S, Ashlock BM, Toomey NL, Diaz LA, Mesri EA, Lossos IS, et al. Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma. J Clin Invest. 2013;123(6):2616–28.
29.
Yazbeck V, Shafer D, Perkins EB, Coppola D, Sokol L, Richards KL, et al. A phase II trial of bortezomib and vorinostat in mantle cell lymphoma and diffuse large B-cell lymphoma. Clin Lymphoma Myeloma Leuk. 2018;18(9):569–75.e1.
30.
Holkova B, Kmieciak M, Bose P, Yazbeck VY, Barr PM, Tombes MB, et al. Phase 1 trial of carfilzomib (PR-171) in combination with vorinostat (SAHA) in patients with relapsed or refractory B-cell lymphomas. Leuk Lymphoma. 2016;57(3):635–43.
31.
Holmberg LA, Green D, Libby E, Becker PS. Bortezomib and vorinostat therapy as maintenance therapy after autologous transplant for multiple myeloma. Acta Haematol. 2020;143(2):146–54.
32.
Crippa F, Holmberg L, Carter RA, Hooper H, Marr KA, Bensinger W, et al. Infectious complications after autologous CD34-selected peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2002;8(5):281–9.
33.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53(282):457–81.
34.
Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, et al.; LYSA Group. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017;377(13):1250–60.
35.
Nanavati C, Mager DE. Sequential exposure of bortezomib and vorinostat is synergistic in multiple myeloma cells. Pharm Res. 2017;34(3):668–79.
36.
Sauter CS, Senechal B, Riviere I, Ni A, Bernal Y, Wang X, et al. CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma. Blood. 2019;134(7):626–35.
37.
Dreyling M, Doorduijn JK, Gine E, Jerkeman M, Walewski J, Hutchings M, et al. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: results from the randomized triangle trial by the European MCL network. Blood. 2022;140(Suppl 1):1–3.
38.
Ibrutinib before and after stem cell transplant in treating patients with relapsed or refractory diffuse large b-cell lymphoma. ClinicalTrials.gov identifier: NCT02443077. Updated: June 18, 2023. Available from: https://www.clinicaltrials.gov/study/NCT02443077 (accessed August 3, 2023).
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