Single-agent bortezomib (B) has shown activity in heavily pretreated patients with relapsed/refractory indolent lymphoma. On the basis of these findings, we performed a phase II study of B combined with rituximab (R) in patients with relapsed follicular lymphoma (FL). Forty-five patients with fairly good prognostic profiles were enrolled from 2007 to 2011 and received a total of 6 cycles of the B+R combination. The endpoints were the overall response rate (ORR), progression-free survival (PFS), duration of remission (DoR), overall survival (OS), and toxicity evaluation. When considering all the enrolled patients the ORR was 64%. At 5 years, the estimated PFS, DoR, and OS were 34, 49, and 70%, respectively. After excluding the 7 R-naïve patients, the ORR was 58%, with a PFS of 19 months. The most common grade >2 toxicities were thrombocytopenia (18%), peripheral neuropathy (13%), and neutropenia (2%). Our study shows the feasibility, long-term efficacy, and excellent tolerability of the B+R combination. We are aware that our study has specific limitations, such as the small sample size consisting of patients with a relatively good prognostic profile. However, because FL patients will be treated with subsequent chemotherapy regimens, a well-tolerated and effective chemotherapy-free therapy could be considered an additional tool for long-term disease control.

Journal Section:
Editor's choice
Keywords:
Rituximab, Relapsed/progressive disease, Follicular lymphoma, Chemotherapy-free regimen, Bortezomib
1.
Aurora V, Winter JN: Current controversies in follicular lymphoma. Blood Rev 2006;20:179-200.
[PubMed]
https://doi.org/10.1016/j.blre.2005.11.003
2.
Corradini P, Astolfi M, Cherasco C, Ladetto M, Voena C, Caracciolo D, Pileri A, Tarella C: Molecular monitoring of minimal residual disease in follicular and mantle cell non-Hodgkin's lymphomas treated with high-dose chemotherapy and peripheral blood progenitor cell autografting. Blood 1997;89:724-731.
[PubMed]
3.
Redman JR, Cabanillas F, Velasquez WS, McLaughlin P, Hagemeister FB, Swan F Jr, Rodriguez MA, Plunkett WK, Keating MJ: Phase II trial of fludarabine phosphate in lymphoma: an effective new agent in low-grade lymphoma. J Clin Oncol 1992;10:790-794.
[PubMed]
4.
Sacchi S, Pozzi S, Marcheselli R, Federico M, Tucci A, Merli F, Orsucci L, Liberati M, Vallisa D, Brugiatelli M; Italian Lymphoma Study Group: Rituximab in combination with fludarabine and cyclophosphamide in the treatment of patients with recurrent follicular lymphoma. Cancer 2007;1:121-128.
[PubMed]
https://doi.org/10.1002/cncr.22740
5.
McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK: Anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998;16:2825-2833.
[PubMed]
6.
Hohloch K, Delaloye AB, Windemuth-Kieselbach C, Gómez-Codina J, Linkesch W, Jurczak W, Cacchione R, Suh C, Zinzani PL, Trümper L: Radioimmunotherapy confers long-term survival to lymphoma patients with acceptable toxicity: registry analysis by the International Radioimmunotherapy Network. J Nucl Med 2011;52:1354-1360.
[PubMed]
https://doi.org/10.2967/jnumed.111.089920
7.
Kaminski MS, Zasadny KR, Francis IR, Fenner MC, Ross CW, Milik AW, Estes J, Tuck M, Regan D, Fisher S, Glenn SD, Wahl RL: Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma. J Clin Oncol 1996;14:1974-1981.
[PubMed]
8.
Blum KA: B-cell receptor pathway modulators in NHL. Hematol Am Soc Hematol Educ Program 2015;2015:82-91.
[PubMed]
https://doi.org/10.1182/asheducation-2015.1.82
9.
Liu Q, Fayad L, Cabanillas F, Hagemeister FB, Ayers GD, Hess M, Romaguera J, Rodriguez MA, Tsimberidou AM, Verstovsek S, Younes A, Pro B, Lee MS, Ayala A, McLaughlin P: Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center. J Clin Oncol 2006;24:1582-1589.
[PubMed]
https://doi.org/10.1200/JCO.2005.03.3696
10.
Sacchi S, Pozzi S, Marcheselli L, Bari A, Luminari S, Angrilli F, Merli F, Vallisa D, Baldini L, Brugiatelli M; Italian Lymphoma Study Group: Introduction of rituximab in front-line and salvage therapies has improved outcome of advanced-stage follicular lymphoma patients. Cancer 2007;109:2077-2082.
[PubMed]
https://doi.org/10.1002/cncr.22649
11.
Hernandez-llizzaliturri FJ, Kotowski A, Czuzman MS: PS341 inhibits cell proliferation, induces apoptosis of and ananches the biological effects of rituximab on non-Hodgkins lymphoma (NHL) cell lines and lymphoma xenografts. 45th Annual Meeting of the America Society of Hematology, San Diego, December 6-9, 2003. Blood Conf 2003;102:903.
12.
Smolewski P, Duechler M, Linke A, Cebula B, Grzybowska-Izydorczyk O, Shehata M, Robak T: Additive cytotoxic effect of bortezomib in combination with anti-CD20 or anti-CD52 monoclonal antibodies on chronic lymphocytic leukemia cells. Leuk Res 2006;30:1521-1529.
[PubMed]
https://doi.org/10.1016/j.leukres.2006.03.005
13.
Reece DE, Sullivan D, Lonial S, Mohrbacher AF, Chatta G, Shustik C, Burris H 3rd, Venkatakrishnan K, Neuwirth R, Riordan WJ, Karol M, von Moltke LL, Acharya M, Zannikos P, Keith Stewart A: Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma. Cancer Chemoter Pharmacol 2011;67:57-67.
[PubMed]
https://doi.org/10.1007/s00280-010-1283-3
14.
Cartron G, Blasco H, Paintaud G, Watier H, Le Guellec C: Pharmacokinetics of rituximsb and its clinical use: thought for the best use? Crit Rev Oncol Hematol 2007;62:43-52.
[PubMed]
https://doi.org/10.1016/j.critrevonc.2006.09.004
15.
Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, Adams J, Esseltine DL, Elliott PJ, Pien CS, Guerciolini R, Anderson JK, Depcik-Smith ND, Bhagat R, Lehman MJ, Novick SC, O'Connor OA, Soignet SL: Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematological malignancies. J Clin Oncol 2002;20:4420-4427.
[PubMed]
https://doi.org/10.1200/JCO.2002.01.133
16.
Goy A, Younes A, McLaughlin P, Pro B, Romaguera JE, Hagemeister F, Fayad L,Dang NH, Samaniego F, Wang M, Broglio K, Samuels B, Gilles F, Sarris AH, Hart S, Trehu E, Schenkein D, Cabanillas F, Rodriguez AM: Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma. J Clin Oncol 2005;23:667-675.
[PubMed]
https://doi.org/10.1111/cas.12735
17.
O'Connor OA, Wright J, Moskowitz C, Muzzy J, MacGregor-Cortelli B, Stubblefield M, Straus D, Portlock C, Hamlin P, Choi E, Dumetrescu O, Esseltine D, Trehu E, Adams J, Schenkein D, Zelenetz AD: 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;23:676-684.
[PubMed]
https://doi.org/10.1200/JCO.2005.02.050
18.
Strauss SJ, Maharaj L, Hoare S, Johnson PW, Radford JA, Vinnecombe S, Millard L, Rohatiner A, Boral A, Trehu E, Schenkein D, Balkwill F, Joel SP, Lister TA: Bortezomib therapy in patients with relapsed or refractory lymphoma: potential correlation of in vitro sensitivity and tumor necrosis factor alpha response with clinical activity. J Clin Oncol 2006;24:2105-2112.
[PubMed]
https://doi.org/10.1200/JCO.2005.04.6789
19.
Di Bella N, Taetle R, Kolibaba K, Boyd T, Raju R, Barrera D, Cochran EW Jr, Dien PY, Lyons R, Schlegel PJ, Vukelja SJ, Boston J, Boehm KA, Wang Y, Asmar L: Results of a phase 2 study of bortezomib in patients with relapsed or refractory indolent lymphoma. Blood 2010;115:475-480.
[PubMed]
https://doi.org/10.1182/blood-2009-08-233155
20.
Gerecitano J, Portlock C, Moskowitz C, Hamlin P, Straus D, Zelenetz AD, Zhang Z, Dumitrescu O, Sarasohn D, Lin D, Pappanicholaou J, Cortelli BM, Neylon E, Hamelers R, Wright J, O'Connor OA: Phase 2 study of weekly bortezomib in mantle cell and follicular lymphoma. Br J Haematol 2009;146:652-655.
[PubMed]
https://doi.org/10.1111/j.1365-2141.2009.07775.x
21.
Ribrag V, Tilly H, Casasnovas O, Bosly A, Bouabdallah R, Delarue R, Boue F, Bron D, Feugier P, Haioun C, Offner F, Coiffier B: Efficacy and toxicity of two schedules of bortezomib in patients with recurrent or refractory follicular lymphoma: a randomised phase II trial from the Groupe d'Etude des Lymphomes dell'Adulte (GELA). Eur J Cancer 2013;49:904-910.
[PubMed]
https://doi.org/10.1016/j.ejca.2012.11.015
22.
Coiffier B, Osmanov EA, Hong X, Scheliga A, Mayer J, Offner F, Rule S, Teixeira A, Walewski J, de Vos S, Crump M, Shpilberg O, Esseltine DL, Zhu E, Enny C, Theocharous P, van de Velde H, Elsayed YA, Zinzani PL; LYM-3001 Study Investigators: Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial. Lancet Oncol 2011;12:773-784.
[PubMed]
https://doi.org/10.1016/S1470-2045(11)70150-4
23.
Zinzani PL, Khuageva NK, Wang H, Garicochea B, Walewski J, Van Hoof A, Soubeyran P, Caballero D, Buckstein R, Esseltine DL, Theocharous P, Enny C, Zhu E, Elsayed YA, Coiffier B: Bortezomib plus rituximab versus rituximab in patients with high-risk, relapsed, rituximab-naïve or rituximab-sensitive follicular lymphoma: subgroup analysis of a randomized phase 3 trial. J Hematol Oncol 2012;5:67.
[PubMed]
https://doi.org/10.1186/1756-8722-5-67
24.
Evens AM, Smith MR, Lossos IS, Helenowski I, Millenson M, Winter JN, Rosen ST, Gordon LI: Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumour burden indolent non-Hodgkin lymphoma: a multicentre phase II study. Br J Haematol 2014;166:514-520.
[PubMed]
https://doi.org/10.1111/bjh.12915
25.
World Health Organization: Classification of Tumors of Haematopoietic and Lymphoid Tissues. Lyon, IARC Press, 2008.
26.
Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, Grillo-López A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, Harris NL, Armitage JO, Carter W, Hoppe R, Canellos GP: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphoma. J Clin Oncol 1999;17:1244-1253.
[PubMed]
27.
Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1-10.
[PubMed]
https://doi.org/10.1016/0197-2456(89)90015-9
28.
Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-481.
https://doi.org/10.1080/01621459.1958.10501452
29.
Solal-Céligny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R, Au WY, Bellei M, Brice P, Caballero D, Coiffier B, Conde-Garcia E, Doyen C, Federico M, Fisher RI, Garcia-Conde JF, Guglielmi C, Hagenbeek A, Haïoun C, Le Blanc M, Lister AT, Lopez-Guillermo A, McLaughlin P, Milpied N, Morel P, Mounier N, Proctor SJ, Rohatiner A, Smith P, Soubeyran P, Tilly H, Vitolo U, Zinzani PL, Zucca E, Montserrat E: Follicular lymphoma international prognostic index. Blood 2004;104:1258-1265.
[PubMed]
https://doi.org/10.1182/blood-2003-12-4434
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