Reduced-dose EPOCH-R chemotherapy for elderly patients with advanced stage diffuse large B cell lymphoma
The standard treatment in elderly patients with diffuse large B cell lymphoma (DLBCL) has not yet been finely established. We investigated the efficacy and safety of rituximab with a reduced-dose of EPOCH chemotherapy in elderly patients who had advanced DLBCL with high IPI scores. The dose of 70% EPOCH was given to patients aged 75 to 79 years, and dose of 50% to patients aged over 80 years. Thirty-one patients with a median age of 79 years (range 75–86 years) were enrolled. Patients received a median of 6 cycle’s chemotherapy. The complete response rate was 71.0%. The 3-year overall survival (OS) and progression-free survival rates were 62.8 and 60.3%, respectively. The most frequent grade 3/4 adverse effects were neutropenia (3 patients, 7 events), febrile neutropenia (3 patients, 5 events), and pulmonary infection (3 patients, 3 events). Our study showed that ECOG score 3–4, bulky disease, β2-MG > 5.0 mg/L, and loss of any IADL are prognostic factors for OS in univariate analysis. In summary, reduced-dose EPOCH-R chemotherapy for very elderly patients is very effective with acceptable toxicities. Our preliminary study may provide an alternative approach to manage very elderly fit patients with advanced and poor risk DLBCL by first-line treatment with reduced-dose EPOCH-R.
KeywordsElderly patients Diffuse large B cell lymphoma Reduced-dose EPOCH-R
The authors thank Mr. Hong-Fei Gu and his team for their contribution to patient education.
This research was supported by the Clinical Research Unit of Xin Hua Hospital; the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20152219 to R Tao); the Shanghai Municipal Education Commission Research and Innovation Grant (13ZZ084 to R Tao).
Compliance with ethical standards
The dose-reduced EPOCH-R protocol was reviewed and approved by the hospital ethics committee. All the patients were fully informed of the adverse drug reactions and they signed an informed consent in accordance with the Declaration of Helsinki.
Conflict of interest
The authors declare that they have no conflict of interest.
- 2.Jayasekara H, Karahalios A, Juneja S, Thursfield V, Farrugia H, English DR, Giles GG (2010) Incidence and survival of lymphohematopoietic neoplasms according to the World Health Organization classification: a population-based study from the Victorian Cancer Registry in Australia. Leuk Lymphoma 51:456–468CrossRefGoogle Scholar
- 6.Meguro A, Ozaki K, Sato K, Oh I, Fujiwara S, Hosonuma R, Sasazaki M, Kikuchi Y, Hirata Y, Yamamoto C, Uesawa M, Kobayashi H, Matsu H, Okabe H, Uehara E, Nishikawa A, Tatara R, Hatano K, Yamamoto C, Matsuyama T, Toshima M, Ueda M, Ohmine K, Suzuki T, Mori M, Nagai T, Muroi K, Ozawa K (2012) Rituximab plus 70% cyclophosphamide, doxorubicin, vincristine and prednisone for Japanese patients with diffuse large B-cell lymphoma aged 70 years and older. Leuk Lymphoma 53:43–49CrossRefGoogle Scholar
- 7.Aoki K, Takahashi T, Tabata S, Kurata M, Matsushita A, Nagai K, Ishikawa T (2013) Efficacy and tolerability of reduced-dose 21-day cycle rituximab and cyclophosphamide, doxorubicin, vincristine and prednisolone therapy for elderly patients with diffuse large B-cell lymphoma. Leuk Lymphoma 54:2441–2447CrossRefGoogle Scholar
- 8.Olivieri A, Gini G, Bocci C, Montanari M, Trappolini S, Olivieri J, Brunori M, Catarini M, Guiducci B, Isidori A, Alesiani F, Giuliodori L, Marcellini M, Visani G, Poloni A, Leoni P (2012) Tailored therapy in an unselected population of 91 elderly patients with DLBCL prospectively evaluated using a simplified CGA. Oncologist 17:663–672CrossRefGoogle Scholar
- 9.Kikuchi M, Nakasone H, Akahoshi Y, Nakano H, Ugai T, Wada H, Yamasaki R, Sakamoto K, Kawamura K, Ishihara Y, Sato M, Ashizawa M, Terasako-Saito K, Kimura SI, Yamazaki R, Kako S, Kanda J, Nishida J, Sekiguchi N, Noto S, Kida M, Hangaishi A, Usuki K, Kanda Y (2015) Reduced-dose (two-thirds) R-CHOP chemotherapy for elderly patients with non-Hodgkin lymphoma. J Chemother 27:99–105CrossRefGoogle Scholar
- 10.Peyrade F, Jardin F, Thieblemont C, Thyss A, Emile JF, Castaigne S, Coiffier B, Haioun C, Bologna S, Fitoussi O, Lepeu G, Fruchart C, Bordessoule D, Blanc M, Delarue R, Janvier M, Salles B, André M, Fournier M, Gaulard P, Tilly H, Groupe d’Etude des Lymphomes de l’Adulte (GELA) investigators (2011) Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Oncol 12:460–468CrossRefGoogle Scholar
- 11.Delarue R, Tilly H, Mounier N, Petrella T, Salles G, Thieblemont C, Bologna S, Ghesquières H, Hacini M, Fruchart C, Ysebaert L, Fermé C, Casasnovas O, van Hoof A, Thyss A, Delmer A, Fitoussi O, Molina TJ, Haioun C, Bosly A (2013) Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol 14:525–533CrossRefGoogle Scholar
- 15.Wilson WH, Dunleavy K, Pittaluga S, Hegde U, Grant N, Steinberg SM, Raffeld M, Gutierrez M, Chabner BA, Staudt L, Jaffe ES, Janik JE (2008) Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin Oncol 26:2717–2724CrossRefGoogle Scholar
- 16.Purroy N, Bergua J, Gallur L, Prieto J, Lopez LA, Sancho JM, García-Marco JA, Castellví J, Montes-Moreno S, Batlle A, de Villambrosia SG, Carnicero F, Ferrando-Lamana L, Piris MA, Lopez A (2015) Long-term follow-up of dose-adjusted EPOCH plus rituximab (DA-EPOCH-R) in untreated patients with poor prognosis large B-cell lymphoma. A phase II study conducted by the Spanish PETHEMA Group. Br J Haematol 169:188–198CrossRefGoogle Scholar
- 17.García-Suárez J, Bañas H, Arribas I, de Miguel D, Pascual T, Burgaleta C (2007) Dose-adjusted EPOCH plus rituximab is an effective regimen in patients with poor-prognostic untreated diffuse large B-cell lymphoma: results from a prospective observational study. Br J Haematol 136:276–285CrossRefGoogle Scholar
- 18.Wilson WH, Jung S-H, Porcu P, Hurd D, Johnson J, Martin SE, Czuczman M, Lai R, Said J, Chadburn A, Jones D, Dunleavy K, Canellos G, Zelenetz AD, Cheson BD, Hsi ED, for the Cancer Leukemia Group B (2012) A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. Haematologica 97:758–765CrossRefGoogle Scholar
- 19.Howlett C, Snedecor SJ, Landsburg DJ, Svoboda J, Chong EA, Schuster SJ, Nasta SD, Feldman T, Rago A, Walsh KM, Weber S, Goy A, Mato A (2015) Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis. Br J Haematol 170:504–514CrossRefGoogle Scholar
- 21.Shikama N, Oguchi M, Isobe K, Nakamura K, Tamaki Y, Hasegawa M, Kodaira T, Sasaki S, Kagami Y (2006) A prospective study of reduced-dose three-course CHOP followed by involved-field radiotherapy for patients 70 years old or more with localized aggressive non-Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 66:217–222CrossRefGoogle Scholar
- 22.Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA, Alliance, Australasian Leukaemia and Lymphoma Group, Eastern Cooperative Oncology Group, European Mantle Cell Lymphoma Consortium, Italian Lymphoma Foundation, European Organisation for Research, Treatment of Cancer/Dutch Hemato-Oncology Group, Grupo Español de Médula Ósea, German High-Grade Lymphoma Study Group, German Hodgkin’s Study Group, Japanese Lymphorra Study Group, Lymphoma Study Association, NCIC Clinical Trials Group, Nordic Lymphoma Study Group, Southwest Oncology Group, United Kingdom National Cancer Research Institute (2014) Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 32:3059–3067CrossRefGoogle Scholar
- 23.Wilson WH, Grossbard ML, Pittaluga S, Cole D, Pearson D, Drbohlav N, Steinberg SM, Little RF, Janik J, Gutierrez M, Raffeld M, Staudt L, Cheson BD, Longo DL, Harris N, Jaffe ES, Chabner BA, Wittes R, Balis F (2002) Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy. Blood 99:2685–2693CrossRefGoogle Scholar
- 24.Advani RH, Chen H, Habermann TM, Morrison VA, Weller EA, Fisher RI, Peterson BA, Gascoyne RD, Horning SJ, Eastern Cooperative Oncology Group, Cancer and Leukemia Group B, Southwest Oncology Group (2010) Comparison of conventional prognostic indices in patients older than 60 years with diffuse large B-cell lymphoma treated with R-CHOP in the US Intergroup Study (ECOG 4494, CALGB 9793): consideration of age greater than 70 years in an elderly prognostic in. Br J Haematol 151:143–151CrossRefGoogle Scholar
- 25.Chihara D, Westin JR, Oki Y, Ahmed MA, Do B, Fayad LE, Hagemeister FB, Romaguera JE, Fanale MA, Lee HJ, Turturro F, Samaniego F, Neelapu SS, Rodriguez MA, Fowler NH, Wang M, Davis RE, Nastoupil LJ (2016) Management strategies and outcomes for very elderly patients with diffuse large B-cell lymphoma. Cancer 122:3145–3151CrossRefGoogle Scholar
- 26.Musolino A, Boggiani D, Panebianco M, Vasini G, Salvagni S, Franciosi V, Ardizzoni A (2011) Activity and safety of dose-adjusted infusional cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy with rituximab in very elderly patients with poor-prognostic untreated diffuse large B-cell non-Hodgkin lymphoma. Cancer 117:964–973CrossRefGoogle Scholar
- 27.Peyrade F, Bologna S, Delwail V, Emile JF, Pascal L, Fermé C, Schiano JM, Coiffier B, Corront B, Farhat H, Fruchart C, Ghesquieres H, Macro M, Tilly H, Choufi B, Delarue R, Fitoussi O, Gabarre J, Haioun C, Jardin F (2017) Combination of ofatumumab and reduced-dose CHOP for diffuse large B-cell lymphomas in patients aged 80 years or older: an open-label, multicentre, single-arm, phase 2 trial from the LYSA group. Lancet Haematol 4(1):e46–e55CrossRefGoogle Scholar
- 31.Nabhan C, Smith SM, Helenowski I, Ramsdale E, Parsons B, Karmali R, Feliciano J, Hanson B, Smith S, McKoy J, Larsen A, Hantel A, Gregory S, Evens AM (2012) Analysis of very elderly (≥80 years) non-hodgkin lymphoma: impact of functional status and co-morbidities on outcome. Br J Haematol 156:196–204CrossRefGoogle Scholar
- 35.Park SI, Grover NS, Olajide O, Asch AS, Wall JG, Richards KL, Sobol AL, Deal AM, Ivanova A, Foster MC, Muss HB, Shea TC (2016) A multicenter phase II study of bendamustine in combination with rituximab in older patients with previously untreated diffuse large B-cell lymphoma. Br J Haematol 175:281–289CrossRefGoogle Scholar