A phase II study on the role of gemcitabine plus romidepsin (GEMRO regimen) in the treatment of relapsed/refractory peripheral T-cell lymphoma patients

Cinzia Pellegrini, Anna Dodero, Annalisa Chiappella, Federico Monaco, Debora Degl'Innocenti, Flavia Salvi, Umberto Vitolo, Lisa Argnani, Paolo Corradini, Pier Luigi Zinzani, Italian Lymphoma Foundation (Fondazione Italiana Linfomi Onlus, FIL), Cinzia Pellegrini, Anna Dodero, Annalisa Chiappella, Federico Monaco, Debora Degl'Innocenti, Flavia Salvi, Umberto Vitolo, Lisa Argnani, Paolo Corradini, Pier Luigi Zinzani, Italian Lymphoma Foundation (Fondazione Italiana Linfomi Onlus, FIL)

Abstract

Background: There is no consensus regarding optimal treatment for peripheral T-cell lymphomas (PTCL), especially in relapsed or refractory cases, which have very poor prognosis and a dismal outcome, with 5-year overall survival of 30 %.

Methods: A multicenter prospective phase II trial was conducted to investigate the role of the combination of gemcitabine plus romidepsin (GEMRO regimen) in relapsed/refractory PTCL, looking for a potential synergistic effect of the two drugs. GEMRO regimen contemplates an induction with romidepsin plus gemcitabine for six 28-day cycles followed by maintenance with romidepsin for patients in at least partial remission. The primary endpoint was the overall response rate (ORR); secondary endpoints were survival, duration of response, and safety of the regimen.

Results: The ORR was 30 % (6/20) with 15 % (3) complete response (CR) rate. Two-year overall survival was 50 % and progression-free survival 11.2 %. Grade ≥3 adverse events were represented by thrombocytopenia (60 %), neutropenia (50 %), and anemia (20 %). Two patients are still in CR with median response duration of 18 months. The majority of non-hematological toxicities were mild and transient. No treatment-related death occurred and no toxicity led to treatment interruption.

Conclusions: GEMRO combination regimen shows efficacy data similar to those of single-agent romidepsin with additional hematologic toxicities. Synergy observed in preclinical phase did not turn into ability to improve clinical outcomes.

Trial registration: The trial was registered under EudraCT 2012-001404-38; ClinicalTrials.gov number, NCT01822886 .

Keywords: Gemcitabine; Peripheral T-cell lymphoma; Refractory; Relapsed; Romidepsin.

Figures

Fig. 1
Fig. 1
Clinical case: positron emission tomography results pre- (a) and post-therapy (b)
Fig. 2
Fig. 2
Overall survival
Fig. 3
Fig. 3
Progression-free survival

References

    1. Kim K, Kim WS, Jung CW, Im YH, Kang WK, Lee MH, Park CH, Ko YH, Ree HJ, Park K. Clinical features of peripheral T-cell lymphomas in 78 patients diagnosed according to the Revised European-American lymphoma (REAL) classification. Eur J Cancer. 2002;38(1):75–81. doi: 10.1016/S0959-8049(01)00344-6.
    1. Lopez-Guillermo A, Cid J, Salar A, Lopez A, Montalban C, Castrillo JM, Gonzalez M, Ribera JM, Brunet S, Garcia-Conde J, Fernandez de Sevilla A, Bosch F, Montserrat E. Peripheral T cell lymphomas: initial features, natural history, and prognostic factors in a series of 174 patients diagnosed according to the R.E.A.L. Classification. Ann Oncol. 1998;9(8):849–55. doi: 10.1023/A:1008418727472.
    1. Reddy NM, Evens AM. Chemotherapeutic advancements in peripheral T-cell lymphoma. Semin Hematol. 2014;51(1):17–24. doi: 10.1053/j.seminhematol.2013.11.006.
    1. Yoon SO, Suh C, Lee DH, Chi HS, Park CJ, Jang SS, Shin HR, Park BH, Huh J. Distribution of lymphoid neoplasms in the Republic of Korea: analysis of 5318 cases according to the World Health Organization classification. Am J Hematol. 2010;85(10):760–4. doi: 10.1002/ajh.21824.
    1. d’Amore F, Relander T, Lauritzsen GF, Jantunen E, Hagberg H, Anderson H, Holte H, Österborg A, Merup M, Brown P, Kuittinen O, Erlanson M, Østenstad B, Fagerli UM, Gadeberg OV, Sundström C, Delabie J, Ralfkiaer E, Vornanen M, Toldbod HE. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol. 2012;30(25):3093–9. doi: 10.1200/JCO.2011.40.2719.
    1. O’Connor OA, Pro B, Pinter-Brown L, Bartlett N, Popplewell L, Coiffier B, Lechowicz MJ, Savage KJ, Shustov AR, Gisselbrecht C, Jacobsen E, Zinzani PL, Furman R, Goy A, Haioun C, Crump M, Zain JM, Hsi E, Boyd A, Horwitz S. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol. 2011;29:1182–9. doi: 10.1200/JCO.2010.29.9024.
    1. Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, Caballero D, Borchmann P, Morschhauser F, Wilhelm M, Pinter-Brown L, Padmanabhan S, Shustov A, Nichols J, Carroll S, Balser J, Balser B, Horwitz S. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol. 2012;30:631–6. doi: 10.1200/JCO.2011.37.4223.
    1. Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, Matous J, Ramchandren R, Fanale M, Connors JM, Yang Y, Sievers EL, Kennedy DA, Shustov A. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30:2190–6. doi: 10.1200/JCO.2011.38.0402.
    1. O’Connor OA, Horwitz S, Masszi T, Van Hoof A, Brown P, Doorduijn J, Hess G, Jurczak W, Knoblauch P, Chawla S, Bhat G, Choi MR, Walewski J, Savage K, Foss F, Allen LF, Shustov A. Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the Pivotal Phase II BELIEF (CLN-19) Study. J Clin Oncol. 2015;33(23):2492–9. doi: 10.1200/JCO.2014.59.2782.
    1. Ogura M, Ishida T, Hatake K, Taniwaki M, Ando K, Tobinai K, Fujimoto K, Yamamoto K, Miyamoto T, Uike N, Tanimoto M, Tsukasaki K, Ishizawa K, Suzumiya J, Inagaki H, Tamura K, Akinaga S, Tomonaga M, Ueda R. Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. J Clin Oncol. 2014;32(11):1157–63. doi: 10.1200/JCO.2013.52.0924.
    1. Dupuis J, Morschhauser F, Ghesquières H, Tilly H, Casasnovas O, Thieblemont C, Ribrag V, Bossard C, Bras FL, Bachy E, Hivert B, Nicolas-Virelizier E, Jardin F, Bastie JN, Amorim S, Lazarovici J, Martin A, Coiffier B. Combination of romidepsin with cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with peripheral T-cell lymphoma: a non-randomised, phase 1b/2 study. Lancet Haematol. 2015;2(4):e160–5. doi: 10.1016/S2352-3026(15)00023-X.
    1. Buckstein R, Fraser G, Cheung M, Kukreti VJj Kuruvilla J, Imrie K, Piliotis E, Pond G, Windsor J, Ghorab Z, Shuoprasad K, Turner R, Meyer RM, Pritchard K, Walker S, Levine M, Crump M. Alemtuzumab and CHOP chemotherapy for the treatment of aggressive histology peripheral t cell lymphomas: a multi-center phase I study. Clin Lymphoma Myeloma Leuk. 2016;16(1):18–28. doi: 10.1016/j.clml.2015.11.008.
    1. Johnston PB, Cashen AF, Nikolinakos PG, Beaven AW, Barta SK, Bhat G, Song T, Choi MR, Allen LF, de Vos S, Oki Y, Deng C, Foss FM. Safe and effective treatment of patients with peripheral T-cell lymphoma (PTCL) with the novel HDAC inhibitor, belinostat, in combination with CHOP: results of the Bel-CHOP Phase 1 Trial. Blood. 2015;124(supplement):abstract 253.
    1. Advani RH, Ansell SM, Lechowicz MJ, Beaven AW, Loberiza F, Carson KR, Evens AM, Foss F, Horwitz S, Pro B, Pinter-Brown LC, Smith SM, Shustov AR, Savage KJ, M Vose J. A phase II study of cyclophosphamide, etoposide, vincristine and prednisone (CEOP) alternating with pralatrexate (P) as front line therapy for patients with peripheral T-cell lymphoma (PTCL): final results from the T- cell consortium trial. Br J Haematol. 2016;172(4):535–44. doi: 10.1111/bjh.13855.
    1. Zinzani PL, Magagnoli M, Bendandi M, Orcioni GF, Gherlinzoni F, Albertini P, Pileri SA, Tura S. Therapy with gemcitabine in pretreated peripheral T-cell lymphoma patients. Ann Oncol. 1998;9(12):1351–3. doi: 10.1023/A:1008409601731.
    1. Zinzani PL, Venturini F, Stefoni V, Fina M, Pellegrini C, Derenzini E, Gandolfi L, Broccoli A, Argnani L, Quirini F, Pileri S, Baccarani M. Gemcitabine as single agent in pretreated T-cell lymphoma patients: evaluation of the long-term outcome. Ann Oncol. 2010;21(4):860–3. doi: 10.1093/annonc/mdp508.
    1. Savage DG, Rule SA, Tighe M, Garrett TJ, Oster MW, Lee RT, Ruiz J, Heitjan D, Keohan ML, Flamm M, Johnson SA. Gemcitabine for relapsed or resistant lymphoma. Ann Oncol. 2000;11(5):595–7. doi: 10.1023/A:1008307528519.
    1. Dong M, He XH, Liu P, Qin Y, Yang JL, Zhou SY, Yang S, Zhang CG, Gui L, Zhou LQ, Shi YK. Gemcitabine-based combination regimen in patients with peripheral T-cell lymphoma. Med Oncol. 2013;30(1):351. doi: 10.1007/s12032-012-0351-4.
    1. Delarue R, Zinzani PL, Hertzberg MS, Kim WS, Caballero D, Pezzutto A, Andre M, Gomes Da Silva M, Gaulard P, Coiffier B. ROCHOP study: a phase III randomized study of CHOP compared to romidepsin-CHOP in untreated peripheral T-cell lymphoma. J Clin Oncol. 2013;31(suppl):TPS8616a.
    1. Fanale MA, Fredrick B, Hagemeister FB, Fayad L, Oki Y, Fowler N, Romaguera J, Shah N, Chuang H, Feng L, Horowitz SB, Wesson E, Hutto TY, Muzzafar T, Samaniego F, Davis RE. A phase I trial of alisertib plus romidepsin for relapsed/refractory aggressive B- and T-cell lymphomas. Blood. 2014;124(supplement):abstract 1744.
    1. Holkova B, Kmieciak M, Bose P, Ma S, Kimball A, Tombes MB, Shrader E, Wan W, Weir-Wiggins C, Stoddert E, Singh AG, Dean A, Conine S, Sankala H, Roberts JD, Shea TC, Grant S. Phase 1 study of bortezomib and romidepsin in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, indolent B-cell lymphoma, peripheral T-cell lymphoma, or cutaneous T-cell lymphoma: updated results. Blood. 2014;124(supplement):abstract 3050.
    1. . Accessed 16 February 2016.
    1. Lunning MA, Ruan J, Nair S, Boruchov AM, Byrne R, Gerecitano JF, Hamlin PA, Inserra B, Leonard J, Lynch P, Matasar MJ, Moskowitz AJ, Moskowitz C, Myskowski PL, Nolan P, Palomba ML, Quefeld C, Straus DJ, Zelenetz AD, Horwitz SM. A phase I/II trial of the combination of romidepsin and lenalidomide in patients with relapsed/refractory lymphoma and myeloma: phase 1 results. J Clin Oncol. 2014;32(supplement):abstract 8582.
    1. Mehta-Shah N, Lunning MA, Ruan J, Niar S, Boruchov AM, Moskovitz AJ, Gerecitano JF, Hamlin PA, Leonard JP, Lynch P, Matasar MJ, Moskovitz C, Portlock C, Younes A, Myskowski P, Nolan P, Palomba ML, Vredenburgh J, Querfeld C, Strauss DJ, Zelenetz A, Schroder H, Rademaker J, Schaffer W, Horwitz SM. A phase I/II trial of the combination of romidepsin and lenalidomide in patients with relapsed/refractory lymphoma and myeloma. Hematol Oncol. 2015;33(supplement):abstract 016.
    1. Accessed 16 February 2016.
    1. Jones SF, Infante JR, Spigel DR, Peacock NW, Thompson DS, Greco FA, McCulloch W, Burris HA., 3rd Phase 1 results from a study of romidepsin in combination with gemcitabine in patients with advanced solid tumors. Cancer Invest. 2012;30(6):481–6. doi: 10.3109/07357907.2012.675382.
    1. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V, International Harmonization Project on Lymphoma Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579–86. doi: 10.1200/JCO.2006.09.2403.
    1. Ellin F, Landström J, Jerkeman M, Relander T. Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish Lymphoma Registry. Blood. 2014;124(10):1570–7. doi: 10.1182/blood-2014-04-573089.
    1. Chai G, Li L, Zhou W, Wu L, Zhao Y, Wang D, Lu S, Yu Y, Wang H, McNutt MA, Hu YG, Chen Y, Yang Y, Wu X, Otterson GA, Zhu WG. HDAC inhibitors act with 5-aza-2'-deoxycytidine to inhibit cell proliferation by suppressing removal of incorporated abases in lung cancer cells. PLoS One. 2008;3(6):e2445. doi: 10.1371/journal.pone.0002445.
    1. Accessed 16 February 2016.
    1. Accessed 16 February 2016.
    1. Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, Caballero D, Morschhauser F, Wilhelm M, Pinter-Brown L, Padmanabhan Iyer S, Shustov A, Nielsen T, Nichols J, Wolfson J, Balser B, Horwitz S. Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma: pivotal study update demonstrates durable responses. J Hematol Oncol. 2014;7:11. doi: 10.1186/1756-8722-7-11.
    1. Mak V, Hamm J, Chhanabhai M, Shenkier T, Klasa R, Sehn LH, Villa D, Gascoyne RD, Connors JM, Savage KJ. Survival of patients with peripheral T-cell lymphoma after first relapse or progression: spectrum of disease and rare long-term survivors. J Clin Oncol. 2013;31(16):1970–6. doi: 10.1200/JCO.2012.44.7524.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit