diffuse large B-cell lymphoma; obinutuzumab; PET-driven
Abstract :
[en] Rituximab plus polychemotherapy is standard of care in diffuse large B-cell lymphoma (DLBCL). GAINED trial
compares obinutuzumab to rituximab. GAINED (NCT01659099) is an open-label, randomized phase 3 trial.
Transplant-eligible patients (18-60yrs) with untreated aged-adjusted international prognostic index (aaIPI) ≥1
DLBCL were randomized (1:1) between obinutuzumab or rituximab. Patients were stratified by aaIPI (1; 2-3)
and chemotherapy regimen (ACVBP; CHOP). Consolidation treatment was determined according to response
assessed by centrally reviewed interim semi-quantitative PET. Responders after cycle 2 and 4 (PET2-/PET4-)
received planned immuno-chemotherapy consolidation. Responders only after cycle 4 (PET2+/4-) received highdose methotrexate plus transplantation. The primary objective was an 8% improvement (HR=0.73; 80% power;
alpha risk 2.5%; one-sided) in 2-year event-free survival (EFS) in the obinutuzumab arm. Events included death,
progression, PET 2 or 4 positivity, modification of planned treatment. From September 20, 2012, 670 patients
were enrolled (obinutuzumab n=336; rituximab n=334). 383 (57.2%) were aaIPI 2-3, 339 (50.6%) received
CHOP and 324 (48.4%) received ACVBP. Median follow-up was 38.7 months. The 2-year EFS were similar in
obinutuzumab and rituximab groups (59.8% vs 56.6%; p=0.123; HR=0.88). The 2-year PFS in the whole cohort
was 83.1% (95%CI 80–85.8). PET2-/4- and PET2+/4- had similar 2-year PFS and OS (89.9% vs 83.9%) and
94.8% vs 92.8%). The 2-year PFS and OS for PET4+ patients were 62% and 83.1%. Grade 3-5 infections were
more frequent in the obinutuzumab arm (21% vs 12%). Obinutuzumab is not superior to rituximab in untreated
aaIPI≥1 DLBCL transplant-eligible patients.
Disciplines :
Hematology
Author, co-author :
Le Gouill, S.
Ghesquieres, H.
Obéric, L.
Morschhauser, F.
Tilly, H.
Ribrag, V.
Lamy, T.
Thieblemont, C.
Maisonneuve, H.G.
Gressin, R.
Bouabdallah, K.
Haioun, C.
Damaj, G.
Fornecker, L.M.
Bouabdallah, R.
Feugier, P.
Sibon, D.
Cartron, G.
BONNET, Christophe ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service d'hématologie clinique
Coiffier, B, Lepage, E, Briere, J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:4 (2002), 235–242.
Habermann, TM, Weller, EA, Morrison, VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 24:19 (2006), 3121–3127.
Pfreundschuh, M, Trümper, L, Osterborg, A, et al., MabThera International Trial Group, CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7:5 (2006), 379–391.
Pfreundschuh, M, Kuhnt, E, Trümper, L, et al., MabThera International Trial (MInT) Group, CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol 12:11 (2011), 1013–1022.
Récher, C, Coiffier, B, Haioun, C, et al., Groupe d'Etude des Lymphomes de l'Adulte, Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet 378:9806 (2011), 1858–1867.
Casasnovas, R-O, Ysebaert, L, Thieblemont, C, et al. FDG-PET-driven consolidation strategy in diffuse large B-cell lymphoma: final results of a randomized phase 2 study. Blood 130:11 (2017), 1315–1326.
Chiappella, A, Martelli, M, Angelucci, E, et al. Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study. Lancet Oncol 18:8 (2017), 1076–1088.
Fitoussi, O, Belhadj, K, Mounier, N, et al. Survival impact of rituximab combined with ACVBP and upfront consolidation autotransplantation in high-risk diffuse large B-cell lymphoma for GELA. Haematologica 96:8 (2011), 1136–1143.
Lin, C, Itti, E, Haioun, C, et al. Early 18F-FDG PET for prediction of prognosis in patients with diffuse large B-cell lymphoma: SUV-based assessment versus visual analysis. J Nucl Med 48:10 (2007), 1626–1632.
Itti, E, Lin, C, Dupuis, J, et al. Prognostic value of interim 18F-FDG PET in patients with diffuse large B-cell lymphoma: SUV-based assessment at 4 cycles of chemotherapy. J Nucl Med 50:4 (2009), 527–533.
Casasnovas, R-O, Meignan, M, Berriolo-Riedinger, A, et al., Groupe d'étude des lymphomes de l'adulte (GELA), SUVmax reduction improves early prognosis value of interim positron emission tomography scans in diffuse large B-cell lymphoma. Blood 118:1 (2011), 37–43.
Le Gouill, S, Casasnovas, R-O, Interim PET-driven strategy in de novo diffuse large B-cell lymphoma: do we trust the driver?. Blood 129:23 (2017), 3059–3070.
Meignan, M, Gallamini, A, Itti, E, Barrington, S, Haioun, C, Polliack, A, Report on the Third International Workshop on Interim Positron Emission Tomography in Lymphoma held in Menton, France, 26-27 September 2011 and Menton 2011 consensus. Leuk Lymphoma 53:10 (2012), 1876–1881.
Marcus, R, Davies, A, Ando, K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 377:14 (2017), 1331–1344.
Vitolo, U, Trněný, M, Belada, D, et al. Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma. J Clin Oncol 35:31 (2017), 3529–3537.
Schmitz, N, Nickelsen, M, Ziepert, M, et al., German High-Grade Lymphoma Study Group (DSHNHL). Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1). Lancet Oncol 13:12 (2012), 1250–1259.
Dührsen, U, Müller, S, Hertenstein, B, et al., PETAL Trial Investigators, Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL): a multicenter, randomized phase III trial. J Clin Oncol 36:20 (2018), 2024–2034.
Casasnovas, R-O, Meignan, M, Berriolo-Riedinger, A, et al. Early interim PET scans in diffuse large B-cell lymphoma: can there be consensus about standardized reporting, and can PET scans guide therapy choices?. Curr Hematol Malig Rep 7:3 (2012), 193–199.
Poeschel, V, Held, G, Ziepert, M, et al., German Lymphoma Alliance, Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial. Lancet 394:10216 (2019), 2271–2281.
Younes, A, Sehn, LH, Johnson, P, et al., PHOENIX investigators, Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol 37:15 (2019), 1285–1295.
Davies, A, Cummin, TE, Barrans, S, et al. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol 20:5 (2019), 649–662.
Vitolo, U, Witzig, T, Gascoyne, R, et al. ROBUST: First report of phase III randomized study of lenalidomide/R-CHOP (R2-CHOP) vs placebo/R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma [abstract]. Hematol Oncol 37:suppl 2 (2019), 36–37 Abstract 05.
Toledano, MN, Desbordes, P, Banjar, A, et al. Combination of baseline FDG PET/CT total metabolic tumour volume and gene expression profile have a robust predictive value in patients with diffuse large B-cell lymphoma. Eur J Nucl Med Mol Imaging 45:5 (2018), 680–688.
Mikhaeel, NG, Smith, D, Dunn, JT, et al. Combination of baseline metabolic tumour volume and early response on PET/CT improves progression-free survival prediction in DLBCL. Eur J Nucl Med Mol Imaging 43:7 (2016), 1209–1219.
Cottereau, A-S, Lanic, H, Mareschal, S, et al. Molecular profile and FDG-PET/CT total metabolic tumor volume improve risk classification at diagnosis for patients with diffuse large B-cell lymphoma. Clin Cancer Res 22:15 (2016), 3801–3809.
Kurtz, DM, Scherer, F, Jin, MC, et al. Circulating tumor DNA measurements as early outcome predictors in diffuse large B-cell lymphoma. J Clin Oncol 36:28 (2018), 2845–2853.
Kurtz, DM, Esfahani, MS, Scherer, F, et al. Dynamic risk profiling using serial tumor biomarkers for personalized outcome prediction. Cell 178:3 (2019), 699–713.e19.