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Curing diffuse large B-cell lymphomas in elderly patients

Published:November 21, 2018DOI:https://doi.org/10.1016/j.ejim.2018.10.003

      Abstract

      In older patients lymphoma is a frequent disease and diffuse large B-cell lymphoma (DLBCL) represents >60% of all lymphomas. Elderly patients with DLBCL are a heterogeneous population and the definition of elderly varies within the literature. Even though the combination of rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone (R-CHOP) is considered standard therapy for DLBCL, management of elderly patients remains challenging. Accurate selection of patients able to tolerate proper immune-chemotherapy is crucial and the comprehensive geriatric assessment based on age, comorbidities and functional abilities of daily living, may help to discriminate among fit, unfit or frail patients. Unfit and frail patients need to be treated with chemotherapy at reduced intensity. Novel compounds with a favorable toxicity profile may represent a promising first-line therapeutic option in combination with standard immune-chemotherapy or as single agent in the relapse/refractory setting.

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      References

        • International Non-Hodgkin's Lymphoma Prognostic Factors P
        A predictive model for aggressive non-Hodgkin's lymphoma.
        N Engl J Med. 1993; 329: 987-994
        • Balducci L.
        • Beghe C.
        The application of the principles of geriatrics to the management of the older person with cancer.
        Crit Rev Oncol Hematol. 2000; 35: 147-154
        • Effect of age on the characteristics and clinical behavior of non-Hodgkin's lymphoma patients
        The Non-Hodgkin's Lymphoma Classification Project.
        Ann Oncol. 1997; 8: 973-978
        • Rosenwald A.
        • Wright G.
        • Chan W.C.
        • Connors J.M.
        • Campo E.
        • Fisher R.I.
        • et al.
        The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma.
        N Engl J Med. 2002; 346: 1937-1947
        • Kramer M.H.
        • Hermans J.
        • Parker J.
        • Krol A.D.
        • Kluin-Nelemans J.C.
        • Haak H.L.
        • et al.
        Clinical significance of bcl2 and p53 protein expression in diffuse large B-cell lymphoma: a population-based study.
        J Clin Oncol. 1996; 14: 2131-2138
        • Offit K.
        • Wong G.
        • Filippa D.A.
        • Tao Y.
        • Chaganti R.S.
        Cytogenetic analysis of 434 consecutively ascertained specimens of non-Hodgkin's lymphoma: clinical correlations.
        Blood. 1991; 77: 1508-1515
        • Klapper W.
        • Kreuz M.
        • Kohler C.W.
        • Burkhardt B.
        • Szczepanowski M.
        • Salaverria I.
        • et al.
        Patient age at diagnosis is associated with the molecular characteristics of diffuse large B-cell lymphoma.
        Blood. 2012; 119: 1882-1887
        • Reiter A.
        • Klapper W.
        Recent advances in the understanding and management of diffuse large B-cell lymphoma in children.
        Br J Haematol. 2008; 142: 329-347
        • Swerdlow S.H.
        • Campo E.
        • Pileri S.A.
        • Harris N.L.
        • Stein H.
        • Siebert R.
        • et al.
        The 2016 revision of the World Health Organization classification of lymphoid neoplasms.
        Blood. 2016; 127: 2375-2390
        • Sawhney R.
        • Sehl M.
        • Naeim A.
        Physiologic aspects of aging: impact on cancer management and decision making, part I.
        Cancer J. 2005; 11: 449-460
        • Martinez-Tapia C.
        • Canoui-Poitrine F.
        • Bastuji-Garin S.
        • Soubeyran P.
        • Mathoulin-Pelissier S.
        • Tournigand C.
        • et al.
        Optimizing the G8 screening tool for older patients with cancer: diagnostic performance and validation of a six-item version.
        Oncologist. 2016; 21: 188-195
        • Tucci A.
        • Ferrari S.
        • Bottelli C.
        • Borlenghi E.
        • Drera M.
        • Rossi G.
        A comprehensive geriatric assessment is more effective than clinical judgment to identify elderly diffuse large cell lymphoma patients who benefit from aggressive therapy.
        Cancer. 2009; 115: 4547-4553
        • Kenis C.
        • Decoster L.
        • Van Puyvelde K.
        • De Greve J.
        • Conings G.
        • Milisen K.
        • et al.
        Performance of two geriatric screening tools in older patients with cancer.
        J Clin Oncol. 2014; 32: 19-26
        • Tucci A.
        • Martelli M.
        • Rigacci L.
        • Riccomagno P.
        • Cabras M.G.
        • Salvi F.
        • et al.
        Comprehensive geriatric assessment is an essential tool to support treatment decisions in elderly patients with diffuse large B-cell lymphoma: a prospective multicenter evaluation in 173 patients by the Lymphoma Italian Foundation (FIL).
        Leuk Lymphoma. 2015; 56: 921-926
        • Sehn L.H.
        • Berry B.
        • Chhanabhai M.
        • Fitzgerald C.
        • Gill K.
        • Hoskins P.
        • et al.
        The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP.
        Blood. 2007; 109: 1857-1861
        • Zhou Z.
        • Sehn L.H.
        • Rademaker A.W.
        • Gordon L.I.
        • Lacasce A.S.
        • Crosby-Thompson A.
        • et al.
        An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era.
        Blood. 2014; 123: 837-842
        • Gobba S.
        • Moccia A.A.
        • Gulden-Sala W.
        • Conconi A.
        • Diem S.
        • Cascione L.
        • et al.
        Outcome of patients older than 80 years with diffuse large B-cell lymphoma (DLBCL) treated with "standard" immunochemotherapy: A large retrospective study from 4 institutions.
        Hematol Oncol. 2018; 36: 84-92
        • Klastersky J.
        • de Naurois J.
        • Rolston K.
        • Rapoport B.
        • Maschmeyer G.
        • Aapro M.
        • et al.
        Management of febrile neutropaenia: ESMO Clinical Practice Guidelines.
        Ann Oncol. 2016; 27: v111-v118
        • Pfreundschuh M.
        How I treat elderly patients with diffuse large B-cell lymphoma.
        Blood. 2010; 116: 5103-5110
        • Pfreundschuh M.
        • Trumper L.
        • Kloess M.
        • Schmits R.
        • Feller A.C.
        • Rube C.
        • et al.
        Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL.
        Blood. 2004; 104: 634-641
        • Peyrade F.
        • Jardin F.
        • Thieblemont C.
        • Thyss A.
        • Emile J.F.
        • Castaigne S.
        • et al.
        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. 2011; 12: 460-468
        • Peyrade F.
        • Bologna S.
        • Delwail V.
        • Emile J.F.
        • Pascal L.
        • Ferme C.
        • et al.
        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. 2017; 4: e46-e55
        • Coiffier B.
        • Lepage E.
        • Briere J.
        • Herbrecht R.
        • Tilly H.
        • Bouabdallah R.
        • et al.
        CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma.
        N Engl J Med. 2002; 346: 235-242
        • Pfreundschuh M.
        • Schubert J.
        • Ziepert M.
        • Schmits R.
        • Mohren M.
        • Lengfelder E.
        • et al.
        Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60).
        Lancet Oncol. 2008; 9: 105-116
        • Delarue R.
        • Tilly H.
        • Mounier N.
        • Petrella T.
        • Salles G.
        • Thieblemont C.
        • et al.
        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. 2013; 14: 525-533
        • Cunningham D.
        • Hawkes E.A.
        • Jack A.
        • Qian W.
        • Smith P.
        • Mouncey P.
        • et al.
        Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles.
        Lancet. 2013; 381: 1817-1826
        • Bonnet C.
        • Fillet G.
        • Mounier N.
        • Ganem G.
        • Molina T.J.
        • Thieblemont C.
        • et al.
        CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: a study by the Groupe d'Etude des Lymphomes de l'Adulte.
        J Clin Oncol. 2007; 25: 787-792
        • Lamy T.
        • Damaj G.
        • Soubeyran P.
        • Gyan E.
        • Cartron G.
        • Bouabdallah K.
        • et al.
        R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma.
        Blood. 2018; 131: 174-181
        • Odejide O.O.
        • Cronin A.M.
        • Davidoff A.J.
        • Lacasce A.S.
        • Abel G.A.
        Limited stage diffuse large B-cell lymphoma: comparative effectiveness of treatment strategies in a large cohort of elderly patients.
        Leuk Lymphoma. 2015; 56: 716-724
        • Held G.
        • Murawski N.
        • Ziepert M.
        • Fleckenstein J.
        • Poschel V.
        • Zwick C.
        • et al.
        Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma.
        J Clin Oncol. 2014; 32: 1112-1118
        • Aoki K.
        • Takahashi T.
        • Tabata S.
        • Kurata M.
        • Matsushita A.
        • Nagai K.
        • et al.
        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. 2013; 54: 2441-2447
        • Iioka F.
        • Izumi K.
        • Kamoda Y.
        • Akasaka T.
        • Ohno H.
        Outcomes of very elderly patients with aggressive B-cell non-Hodgkin lymphoma treated with reduced-dose chemotherapy.
        Int J Clin Oncol. 2016; 21: 498-505
        • Spina M.
        • Balzarotti M.
        • Uziel L.
        • Ferreri A.J.
        • Fratino L.
        • Magagnoli M.
        • et al.
        Modulated chemotherapy according to modified comprehensive geriatric assessment in 100 consecutive elderly patients with diffuse large B-cell lymphoma.
        Oncologist. 2012; 17: 838-846
        • Luminari S.
        • Montanini A.
        • Caballero D.
        • Bologna S.
        • Notter M.
        • Dyer M.J.
        • et al.
        Nonpegylated liposomal doxorubicin (MyocetTM) combination (R-COMP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL): results from the phase II EUR018 trial.
        Ann Oncol. 2010; 21: 1492-1499
        • Fridrik M.A.
        • Jaeger U.
        • Petzer A.
        • Willenbacher W.
        • Keil F.
        • Lang A.
        • et al.
        Cardiotoxicity with rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone compared to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in frontline treatment of patients with diffuse large B-cell lymphoma: A randomised phase-III study from the Austrian Cancer Drug Therapy Working Group [Arbeitsgemeinschaft Medikamentose Tumortherapie AGMT](NHL-14).
        Eur J Cancer. 2016; 58: 112-121
        • Merli F.
        • Luminari S.
        • Rossi G.
        • Mammi C.
        • Marcheselli L.
        • Tucci A.
        • et al.
        Cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab versus epirubicin, cyclophosphamide, vinblastine, prednisone and rituximab for the initial treatment of elderly "fit" patients with diffuse large B-cell lymphoma: results from the ANZINTER3 trial of the Intergruppo Italiano Linfomi.
        Leuk Lymphoma. 2012; 53: 581-588
        • Hagemeister F.
        • Rodriguez M.A.
        • Deitcher S.R.
        • Younes A.
        • Fayad L.
        • Goy A.
        • et al.
        Long term results of a phase 2 study of vincristine sulfate liposome injection (Marqibo((R))) substituted for non-liposomal vincristine in cyclophosphamide, doxorubicin, vincristine, prednisone with or without rituximab for patients with untreated aggressive non-Hodgkin lymphomas.
        Br J Haematol. 2013; 162: 631-638
        • Musolino A.
        • Boggiani D.
        • Panebianco M.
        • Vasini G.
        • Salvagni S.
        • Franciosi V.
        • et al.
        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. 2011; 117: 964-973
        • Pfreundschuh M.
        • Muller C.
        • Zeynalova S.
        • Kuhnt E.
        • Wiesen M.H.
        • Held G.
        • et al.
        Suboptimal dosing of rituximab in male and female patients with DLBCL.
        Blood. 2014; 123: 640-646
        • Pfreundschuh M.
        • Poeschel V.
        • Zeynalova S.
        • Hanel M.
        • Held G.
        • Schmitz N.
        • et al.
        Optimization of rituximab for the treatment of diffuse large B-cell lymphoma (II): extended rituximab exposure time in the SMARTE-R-CHOP-14 trial of the german high-grade non-Hodgkin lymphoma study group.
        J Clin Oncol. 2014; 32: 4127-4133
        • Fields P.A.
        • Townsend W.
        • Webb A.
        • Counsell N.
        • Pocock C.
        • Smith P.
        • et al.
        De novo treatment of diffuse large B-cell lymphoma with rituximab, cyclophosphamide, vincristine, gemcitabine, and prednisolone in patients with cardiac comorbidity: a United Kingdom National Cancer Research Institute trial.
        J Clin Oncol. 2014; 32: 282-287
        • Moccia A.A.
        • Hoskins P.
        • et al.
        R-CHOP with etoposide substituted for doxorubicin (RCEOP): Excellent outcome in diffuse large B cell lymphoma for patients with a contraindication to anthracyclines. (abstr 408).
        Blood. 2009; 114
        • Rashidi A.
        • Oak E.
        • Carson K.R.
        • Wagner-Johnston N.D.
        • Kreisel F.
        • Bartlett N.L.
        Outcomes with R-CEOP for R-CHOP-ineligible patients with diffuse large B-cell lymphoma are highly dependent on cell of origin defined by Hans criteria.
        Leuk Lymphoma. 2016; 57: 1191-1193
        • Weidmann E.
        • Neumann A.
        • Fauth F.
        • Atmaca A.
        • Al-Batran S.E.
        • Pauligk C.
        • et al.
        Phase II study of bendamustine in combination with rituximab as first-line treatment in patients 80 years or older with aggressive B-cell lymphomas.
        Ann Oncol. 2011; 22: 1839-1844
        • Park S.I.
        • Grover N.S.
        • Olajide O.
        • Asch A.S.
        • Wall J.G.
        • Richards K.L.
        • et al.
        A phase II trial of bendamustine in combination with rituximab in older patients with previously untreated diffuse large B-cell lymphoma.
        Br J Haematol. 2016; 175: 281-289
        • Ohmachi K.
        • Niitsu N.
        • Uchida T.
        • Kim S.J.
        • Ando K.
        • Takahashi N.
        • et al.
        Multicenter phase II study of bendamustine plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma.
        J Clin Oncol. 2013; 31: 2103-2109
        • Crump M.
        • Kuruvilla J.
        • Couban S.
        • MacDonald D.A.
        • Kukreti V.
        • Kouroukis C.T.
        • et al.
        Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12..
        J Clin Oncol. 2014; 32: 3490-3496
        • Moccia A.A.
        • Hitz F.
        • Hoskins P.
        • Klasa R.
        • Power M.M.
        • Savage K.J.
        • et al.
        Gemcitabine, dexamethasone, and cisplatin (GDP) is an effective and well-tolerated salvage therapy for relapsed/refractory diffuse large B-cell lymphoma and Hodgkin lymphoma.
        Leuk Lymphoma. 2017; 58: 324-332
        • Lopez A.
        • Gutierrez A.
        • Palacios A.
        • Blancas I.
        • Navarrete M.
        • Morey M.
        • et al.
        GEMOX-R regimen is a highly effective salvage regimen in patients with refractory/relapsing diffuse large-cell lymphoma: a phase II study.
        Eur J Haematol. 2008; 80: 127-132
        • Chiappella A.
        • Tucci A.
        • Castellino A.
        • Pavone V.
        • Baldi I.
        • Carella A.M.
        • et al.
        Lenalidomide plus cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab is safe and effective in untreated, elderly patients with diffuse large B-cell lymphoma: a phase I study by the Fondazione Italiana Linfomi.
        Haematologica. 2013; 98: 1732-1738
        • Nowakowski G.S.
        • Laplant B.
        • Habermann T.M.
        • Rivera C.E.
        • Macon W.R.
        • Inwards D.J.
        • et al.
        Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study.
        Leukemia. 2011; 25: 1877-1881
        • Thieblemont C.
        • Tilly H.
        • Gomes Da Silva M.
        • Casasnovas R.O.
        • Fruchart C.
        • Morschhauser F.
        • et al.
        Lenalidomide Maintenance Compared With Placebo in Responding Elderly Patients With Diffuse Large B-Cell Lymphoma Treated With First-Line Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone.
        J Clin Oncol. 2017; 35: 2473-2481
        • Wilson W.H.
        • Young R.M.
        • Schmitz R.
        • Yang Y.
        • Pittaluga S.
        • Wright G.
        • et al.
        Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma.
        Nat Med. 2015; 21: 922-926
        • Witzig T.E.
        • Reeder C.B.
        • Laplant B.R.
        • Gupta M.
        • Johnston P.B.
        • Micallef I.N.
        • et al.
        A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma.
        Leukemia. 2011; 25: 341-347
        • Habermann T.M.
        • Weller E.A.
        • Morrison V.A.
        • Gascoyne R.D.
        • Cassileth P.A.
        • Cohn J.B.
        • et al.
        Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma.
        J Clin Oncol. 2006; 24: 3121-3127