An evaluation based on relative treatment intensity in older patients treated with reduced-dose R-THP-COP therapy for diffuse large B-cell lymphoma: A multicenter retrospective cohort study

Published:October 31, 2022DOI:



      The number of older patients with diffuse large B-cell lymphoma (DLBCL) is increasing. Although the standard treatment for newly diagnosed younger patients with DLBCL has been established, no consensus has been reached regarding the optimal chemotherapy intensity and regimen for older patients with DLBCL. In addition, no method for evaluating treatment intensity in retrospective studies when different numbers of chemotherapy courses are administered has been elucidated.

      Materials and Methods

      A multicenter retrospective analysis was conducted to evaluate the outcomes of a reduced-dose R-THP-COP regimen, which included 30 mg/m2 of pirarubicin, in 54 patients with DLBCL who were aged ≥75. To assess treatment intensity, we defined the relative treatment intensity (RTI) as the number of courses administered multiplied by the relative dose intensity (RDI).


      The estimated four-year overall survival rates (OS) of the patients aged 75–80 and ≥ 80 were 55.1% and 60.6%, respectively. There was no significant difference in four-year OS between these age groups. In our cohort, there was no significant difference in the estimated four-year OS between the patients who received reduced-dose R-THP-COP at an RDI of ≥61% and those that received it at an RDI of <61% (P = 0.35). On the other hand, the patients who received reduced-dose R-THP-COP at an RTI of ≥2.7 exhibited a significantly higher estimated four-year OS than those treated at an RTI of <2.7 (68.5% vs. 28.7%; P < 0.001). Multivariate analysis revealed that the RTI was a significant independent predictor of OS. The cumulative incidence of treatment-related mortality (TRM) at one year was 4.2% and 3.4% in the 75–80 and ≥ 80 age groups, respectively. The cumulative incidence of TRM was significantly worse among the patients with Charlson Comorbidity Index (CCI) scores of ≥2 than among those with CCI scores of 0 or 1.


      Our study suggests that the reduced-dose R-THP-COP regimen is a suitable treatment option for older patients with DLBCL, especially those with CCI scores of <2. Our study also showed that the RTI may be a valuable tool for assessing treatment intensity in retrospective studies involving older patients.


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        • 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
        • Morton L.M.
        • Wang S.S.
        • Devesa S.S.
        • Hartge P.
        • Weisenburger D.D.
        • Linet M.S.
        Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001.
        Blood. 2006; 107: 265-276
        • Issa D.E.
        • van de Schans S.A.
        • Chamuleau M.E.
        • Karim-Kos H.E.
        • Wondergem M.
        • Huijgens P.C.
        • et al.
        Trends in incidence, treatment and survival of aggressive B-cell lymphoma in the Netherlands 1989-2010.
        Haematologica. 2015; 100: 525-533
        • Muto R.
        • Miyoshi H.
        • Sato K.
        • Furuta T.
        • Muta H.
        • Kawamoto K.
        • et al.
        Epidemiology and secular trends of malignant lymphoma in Japan: analysis of 9426 cases according to the World Health Organization classification.
        Cancer Med. 2018; 7: 5843-5858
        • Carson K.R.
        • Riedell P.
        • Lynch R.
        • Nabhan C.
        • Wildes T.M.
        • Liu W.
        • et al.
        Comparative effectiveness of anthracycline-containing chemotherapy in United States veterans age 80 and older with diffuse large B-cell lymphoma.
        J. Geriatr. Oncol. 2015; 6: 211-218
        • Juul M.B.
        • Jensen P.H.
        • Engberg H.
        • Wehberg S.
        • Dessau-Arp A.
        • Haziri D.
        • et al.
        Treatment strategies and outcomes in diffuse large B-cell lymphoma among 1011 patients aged 75 years or older: a Danish population-based cohort study.
        Eur. J. Cancer. 2018; 99: 86-96
        • Akhtar O.S.
        • Huang L.W.
        • Tsang M.
        • Torka P.
        • Loh K.P.
        • Morrison V.A.
        • et al.
        Geriatric assessment in older adults with non-Hodgkin lymphoma: a young International Society of Geriatric Oncology (YSIOG) review paper.
        J. Geriatr. Oncol. 2022; 13: 572-581
        • Bosly A.
        • Bron D.
        • Van Hoof A.
        • De Bock R.
        • Berneman Z.
        • Ferrant A.
        • et al.
        Achievement of optimal average relative dose intensity and correlation with survival in diffuse large B-cell lymphoma patients treated with CHOP.
        Ann. Hematol. 2008; 87: 277-283
        • Eyre T.A.
        • Salisbury R.
        • Eyre D.W.
        • Watson C.
        • Collins G.P.
        • Hatton C.S.
        Results of a large retrospective analysis of the effect of intended dose intensity of R-CHOP on outcome in a cohort of consecutive, unselected elderly patients with de novo diffuse large B cell lymphoma.
        Br. J. Haematol. 2016; 173: 487-491
        • 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
        • Tilly H.
        • Gomes da Silva M.
        • Vitolo U.
        • Jack A.
        • Meignan M.
        • Lopez-Guillermo A.
        • et al.
        Diffuse large B-cell lymphoma (DLBCL): ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
        Ann. Oncol. 2015; 26: v116-v125
        • Buske C.
        • Hutchings M.
        • Ladetto M.
        • Goede V.
        • Mey U.
        • Soubeyran P.
        • et al.
        ESMO consensus conference on malignant lymphoma: general perspectives and recommendations for the clinical management of the elderly patient with malignant lymphoma.
        Ann. Oncol. 2018; 29: 544-562
        • Bataillard E.J.
        • Cheah C.Y.
        • Maurer M.J.
        • Khurana A.
        • Eyre T.A.
        • El-Galaly T.C.
        Impact of R-CHOP dose intensity on survival outcomes in diffuse large B-cell lymphoma: a systematic review.
        Blood Adv. 2021; 5: 2426-2437
        • Eyre T.A.
        • Martinez-Calle N.
        • Hildyard C.
        • Eyre D.W.
        • Plaschkes H.
        • Griffith J.
        • et al.
        Impact of intended and relative dose intensity of R-CHOP in a large, consecutive cohort of elderly diffuse large B-cell lymphoma patients treated with curative intent: no difference in cumulative incidence of relapse comparing patients by age.
        J. Intern. Med. 2019; 285: 681-692
        • Lee S.
        • Fujita K.
        • Negoro E.
        • Morishita T.
        • Oiwa K.
        • Tsukasaki H.
        • et al.
        Impact of relative dose intensity of standard regimens on survival in elderly patients aged 80 years and older with diffuse large B-cell lymphoma.
        Haematologica. 2020; 105: e415-e418
        • Zhai L.
        • Guo C.
        • Cao Y.
        • Xiao J.
        • Fu X.
        • Huang J.
        • et al.
        Long-term results of pirarubicin versus doxorubicin in combination chemotherapy for aggressive non-Hodgkin’s lymphoma: single center, 15-year experience.
        Int. J. Hematol. 2010; 91: 78-86
        • Hara T.
        • Tsurumi H.
        • Goto N.
        • Kitagawa J.
        • Kanemura N.
        • Yoshikawa T.
        • et al.
        Phase II study of rituximab combined with THP-COP as first-line therapy for patients younger than 70 years with diffuse large B cell lymphoma.
        J. Cancer Res. Clin. Oncol. 2010; 136: 65-70
        • Tsurumi H.
        • Hara T.
        • Goto N.
        • Kanemura N.
        • Kasahara S.
        • Sawada M.
        • et al.
        A phase II study of a THP-COP regimen for the treatment of elderly patients aged 70 years or older with diffuse large B-cell lymphoma.
        Hematol. Oncol. 2007; 25: 107-114
        • Yamaguchi H.
        • Hirakawa T.
        • Inokuchi K.
        Importance of relative dose intensity in chemotherapy for diffuse large B-cell lymphoma.
        J. Clin. Exp. Hematop. 2011; 51: 1-5
        • Dlugosz-Danecka M.
        • Szmit S.
        • Ogorka T.
        • Skotnicki A.B.
        • Jurczak W.
        The average relative dose intensity of R-CHOP is an independent factor determining favorable overall survival in diffuse large B-cell lymphoma patients.
        Cancer Med. 2019; 8: 1103-1109
        • Kanda Y.
        Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics.
        Bone Marrow Transplant. 2013; 48: 452-458
        • Meguro A.
        • Ozaki K.
        • Sato K.
        • Oh I.
        • Fujiwara S.
        • Hosonuma R.
        • et al.
        Rituximab plus 70% cyclophosphamide, doxorubicin, vincristine and prednisone for Japanese patients with diffuse large B-cell lymphoma aged 70 years and older.
        Leuk. Lymphoma. 2012; 53: 43-49
        • Briand M.
        • Gerard S.
        • Gauthier M.
        • Garric M.
        • Steinmeyer Z.
        • Balardy L.
        Impact of therapeutic management and geriatric evaluation on patient of eighty years and older with diffuse large B-cell lymphoma on survival: a systematic review.
        Eur. J. Haematol. 2022; 108: 3-17
        • Beygi S.
        • Sadashiv S.
        • Reilly J.B.
        • Khan C.
        • Lister J.
        Frontline treatment of diffuse large B-cell lymphoma in elderly: a systematic review of clinical trials in post-rituximab era.
        Leuk. Lymphoma. 2018; 59: 2847-2861
        • 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
        • Oberic L.
        • Peyrade F.
        • Puyade M.
        • Bonnet C.
        • Dartigues-Cuilleres P.
        • Fabiani B.
        • et al.
        Subcutaneous rituximab-MiniCHOP compared with subcutaneous rituximab-MiniCHOP plus Lenalidomide in diffuse large B-cell lymphoma for patients age 80 years or older.
        J. Clin. Oncol. 2021; 39: 1203-1213
        • Hirakawa T.
        • Yamaguchi H.
        • Yokose N.
        • Gomi S.
        • Inokuchi K.
        • Dan K.
        Importance of maintaining the relative dose intensity of CHOP-like regimens combined with rituximab in patients with diffuse large B-cell lymphoma.
        Ann. Hematol. 2010; 89: 897-904
        • Kanemasa Y.
        • Shimoyama T.
        • Sasaki Y.
        • Tamura M.
        • Sawada T.
        • Omuro Y.
        • et al.
        The impacts of initial and relative dose intensity of R-CHOP on outcomes of elderly patients with diffuse large B-cell lymphoma.
        Leuk. Lymphoma. 2017; 58: 736-739
        • Zettl F.
        • Ziepert M.
        • Altmann B.
        • Zeynalova S.
        • Held G.
        • Poschel V.
        • et al.
        Age-dependent increase of treatment-related mortality in older patients with aggressive B cell lymphoma: analysis of outcome, treatment feasibility, and toxicity in 1171 elderly patients with aggressive B cell lymphoma-data from phase II and III trials of the DSHNHL (German high-grade non-Hodgkin’s lymphoma study group).
        Ann. Hematol. 2021; 100: 1031-1038
        • Williams J.N.
        • Rai A.
        • Lipscomb J.
        • Koff J.L.
        • Nastoupil L.J.
        • Flowers C.R.
        Disease characteristics, patterns of care, and survival in very elderly patients with diffuse large B-cell lymphoma.
        Cancer. 2015; 121: 1800-1808
        • Umezawa H.
        • Takahashi Y.
        • Kinoshita M.
        • Naganawa H.
        • Masuda T.
        • Ishizuka M.
        • et al.
        Tetrahydropyranyl derivatives of daunomycin and adriamycin.
        J. Antibiot. (Tokyo). 1979; 32: 1082-1084
        • Kitamura K.
        • Takaku F.
        Pirarubicin, a novel derivative of doxorubicin. THP-COP therapy for non-Hodgkin’s lymphoma in the elderly.
        Am. J. Clin. Oncol. 1990; 13: S15-S19
        • Mori M.
        • Kitamura K.
        • Masuda M.
        • Hotta T.
        • Miyazaki T.
        • Miura A.B.
        • et al.
        Long-term results of a multicenter randomized, comparative trial of modified CHOP versus THP-COP versus THP-COPE regimens in elderly patients with non-Hodgkin’s lymphoma.
        Int. J. Hematol. 2005; 81: 246-254
        • Kasahara S.
        • Hara T.
        • Tsurumi H.
        • Goto N.
        • Kitagawa J.
        • Kanemura N.
        • et al.
        Phase II study of the tetrahydropyranyl adriamycin-cyclophosphamide, vincristine, and prednisolone regimen combined with rituximab as first-line treatment for elderly patients with diffuse large B-cell lymphoma.
        Leuk. Lymphoma. 2011; 52: 629-634
        • 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
        • Araie H.
        • Sakamaki I.
        • Matsuda Y.
        • Tai K.
        • Ikegaya S.
        • Itoh K.
        • et al.
        3A comparison between R-THP-COP and R-CHOP regimens for the treatment of diffuse large B-cell lymphoma in old patients: a single-institution analysis.
        Intern. Med. 2017; 56: 2407-2413
        • Hara T.
        • Yoshikawa T.
        • Goto H.
        • Sawada M.
        • Yamada T.
        • Fukuno K.
        • et al.
        R-THP-COP versus R-CHOP in patients younger than 70 years with untreated diffuse large B cell lymphoma: a randomized, open-label, noninferiority phase 3 trial.
        Hematol. Oncol. 2018; 36: 638-644
        • Niitsu N.
        • Umeda M.
        Response and adverse drug reactions to combination chemotherapy in elderly patients with aggressive non-Hodgkin’s lymphoma: comparison of CHOP, COP-BLAM, COP-BLAM III, and THP-COPBLM.
        Eur. J. Haematol. 1999; 63: 337-344
        • Shimomura Y.
        • Baba R.
        • Watanabe A.
        • Horikoshi Y.
        • Asami K.
        • Hyakuna N.
        • et al.
        Assessment of late cardiotoxicity of pirarubicin (THP) in children with acute lymphoblastic leukemia.
        Pediatr. Blood Cancer. 2011; 57: 461-466
        • Salz T.
        • Zabor E.C.
        • de Nully Brown P.
        • Dalton S.O.
        • Raghunathan N.J.
        • Matasar M.J.
        • et al.
        Preexisting cardiovascular risk and subsequent heart failure among non-Hodgkin lymphoma survivors.
        J. Clin. Oncol. 2017; 35: 3837-3843
        • Boddicker N.J.
        • Larson M.C.
        • Castellino A.
        • Herrmann J.
        • Inwards D.J.
        • Thanarajasingam G.
        • et al.
        Anthracycline treatment, cardiovascular risk factors and the cumulative incidence of cardiovascular disease in a cohort of newly diagnosed lymphoma patients from the modern treatment era.
        Am. J. Hematol. 2021; 96: 979-988
        • Di M.
        • Huntington S.F.
        • Olszewski A.J.
        Challenges and opportunities in the Management of Diffuse Large B-cell lymphoma in older patients.
        Oncologist. 2021; 26: 120-132