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Upfront autologous stem cell transplantation for untreated diffuse large B cell lymphoma patients in rituximab era: a systematic review and meta-analysis

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Abstract

To assess the survival outcomes and adverse events (AEs) of high-intermediate- or high-risk patients with diffuse large B cell lymphoma (DLBCL) who underwent conventional chemotherapy plus rituximab with or without first-line autologous stem cell transplantation (ASCT). Related studies published on Medline, Embase, Cochrane Library, and Web of science were searched, comprising both retrospective and randomized clinical trials (RCTs). The primary endpoints were overall survival (OS) and progression-free survival (PFS). The meta-analysis was performed using the software RevMan v5.3. Four RCTs and six retrospective trials with a total of 1811 patients were identified. Pooled data indicated that conventional chemotherapy plus rituximab followed by ASCT as the first-line therapy contributed to better PFS (HR = 0.73, 95% CI 0.62–0.86, p = 0.0002) but did not significantly improve OS (HR = 0.74, 95% CI 0.55–1.01, p = 0.06) of high-intermediate/high-risk patients. Subgroup analyses of patients with complete remission after induction chemotherapy may benefit from the upfront ASCT (OS, HR = 0.48, 95% CI 0.28–0.82, p = 0.008). The incidences of grade ≥ 3 hematological and non-hematological AEs occurred more frequently in the transplantation group. High-intermediate or high-risk untreated patients with DLBCL only achieved short-term survival benefit with the upfront ASCT.

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References

  1. Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR (2016) 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin 66(6):443–459. https://doi.org/10.3322/caac.21357

    Article  PubMed  Google Scholar 

  2. Gu X, Zheng R, Xia C, Zeng H, Zhang S, Zou X, Yang Z, Li H, Chen W (2018) Interactions between life expectancy and the incidence and mortality rates of cancer in China: a population-based cluster analysis. Cancer Commun (Lond) 38(1):44. https://doi.org/10.1186/s40880-018-0308-x

    Article  Google Scholar 

  3. Sehn LH, Donaldson J, Chhanabhai M, Fitzgerald C, Gill K, Klasa R, MacPherson N, O’Reilly S, Spinelli JJ, Sutherland J, Wilson KS, Gascoyne RD, Connors JM (2005) Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol Off J Am Soc Clin Oncol 23(22):5027–5033. https://doi.org/10.1200/jco.2005.09.137

    Article  Google Scholar 

  4. Nowakowski GS, LaPlant B, Macon WR, Reeder CB, Foran JM, Nelson GD, Thompson CA, Rivera CE, Inwards DJ, Micallef IN, Johnston PB, Porrata LF, Ansell SM, Gascoyne RD, Habermann TM, Witzig TE (2015) Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-Cell lymphoma: a phase II study. J Clin Oncol Off J Am Soc Clin Oncol 33(3):251–257. https://doi.org/10.1200/jco.2014.55.5714

    Article  Google Scholar 

  5. Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Briere J, Moskowitz CH, Schmitz N (2010) Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol Off J Am Soc Clin Oncol 28(27):4184–4190. https://doi.org/10.1200/jco.2010.28.1618

    Article  Google Scholar 

  6. Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D, Sonneveld P, Gisselbrecht C, Cahn JY, Harousseau JL et al (1995) Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 333(23):1540–1545. https://doi.org/10.1056/nejm199512073332305

    Article  PubMed  Google Scholar 

  7. Martelli M, Gherlinzoni F, De Renzo A, Zinzani PL, De Vivo A, Cantonetti M, Falini B, Storti S, Meloni G, Rizzo M, Molinari AL, Lauria F, Moretti L, Lauta VM, Mazza P, Guardigni L, Pescarmona E, Pileri SA, Mandelli F, Tura S (2003) Early autologous stem-cell transplantation versus conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin’s lymphoma: an Italian multicenter randomized trial. J Clin Oncol Off J Am Soc Clin Oncol 21(7):1255–1262. https://doi.org/10.1200/jco.2003.01.117

    Article  Google Scholar 

  8. Milpied N, Deconinck E, Gaillard F, Delwail V, Foussard C, Berthou C, Gressin R, Lucas V, Colombat P, Harousseau JL (2004) Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 350(13):1287–1295. https://doi.org/10.1056/NEJMoa031770

    Article  PubMed  Google Scholar 

  9. Gisselbrecht C, Lepage E, Molina T, Quesnel B, Fillet G, Lederlin P, Coiffier B, Tilly H, Gabarre J, Guilmin F, Hermine O, Reyes F (2002) Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol Off J Am Soc Clin Oncol 20(10):2472–2479. https://doi.org/10.1200/jco.2002.02.125

    Article  Google Scholar 

  10. Greb A, Bohlius J, Trelle S, Schiefer D, De Souza CA, Gisselbrecht C, Intragumtornchai T, Kaiser U, Kluin-Nelemans HC, Martelli M, Milpied NJ, Santini G, Verdonck LF, Vitolo U, Schwarzer G, Engert A (2007) High-dose chemotherapy with autologous stem cell support in first-line treatment of aggressive non-Hodgkin lymphoma-results of a comprehensive meta-analysis. Cancer Treat Rev 33(4):338–346. https://doi.org/10.1016/j.ctrv.2007.02.002

    Article  PubMed  Google Scholar 

  11. Pfreundschuh M, Kuhnt E, Trumper L, Osterborg A, Trneny M, Shepherd L, Gill DS, Walewski J, Pettengell R, Jaeger U, Zinzani PL, Shpilberg O, Kvaloy S, de Nully BP, Stahel R, Milpied N, Lopez-Guillermo A, Poeschel V, Grass S, Loeffler M, Murawski N (2011) 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):1013–1022. https://doi.org/10.1016/s1470-2045(11)70235-2

    Article  PubMed  Google Scholar 

  12. Gouill SL, Milpied NJ, Lamy T, Delwail V, Gressin R, Guyotat D, Damaj GL, Foussard C, Cartron G, Maisonneuve HJJoCOOJotASoCO (2011) First-line rituximab (R) high-dose therapy (R-HDT) versus R-CHOP14 for young adults with diffuse large B-cell lymphoma: Preliminary results of the GOELAMS 075 prospective multicenter randomized trial. 29 (15_suppl):8003

  13. Stiff PJ, Unger JM, Cook JR, Constine LS, Couban S, Stewart DA, Shea TC, Porcu P, Winter JN, Kahl BS, Miller TP, Tubbs RR, Marcellus D, Friedberg JW, Barton KP, Mills GM, LeBlanc M, Rimsza LM, Forman SJ, Fisher RI (2013) Autologous transplantation as consolidation for aggressive non-Hodgkin’s lymphoma. N Engl J Med 369(18):1681–1690. https://doi.org/10.1056/NEJMoa1301077

    Article  PubMed  PubMed Central  Google Scholar 

  14. Cortelazzo S, Tarella C, Gianni AM, Ladetto M, Barbui AM, Rossi A, Gritti G, Corradini P, Di Nicola M, Patti C, Mulé A, Zanni M, Zoli V, Billio A, Piccin A, Negri G, Castellino C, Di Raimondo F, Ferreri AJM, Benedetti F, La Nasa G, Gini G, Trentin L, Frezzato M, Flenghi L, Falorio S, Chilosi M, Bruna R, Tabanelli V, Pileri S, Masciulli A, Delaini F, Boschini C, Rambaldi A (2016) Randomized trial comparing R-CHOP versus high-dose sequential chemotherapy in high-risk patients with diffuse large B-cell lymphomas. J Clin Oncol 34(33):4015–4022. https://doi.org/10.1200/jco.2016.67.2980

    Article  PubMed  Google Scholar 

  15. Yoon JH, Kim JW, Jeon YW, Lee SE, Eom KS, Kim YJ, Lee S, Kim HJ, Min CK, Lee JW, Min WS, Park CW, Cho SG (2015) Role of frontline autologous stem cell transplantation in young, high-risk diffuse large B-cell lymphoma patients. Korean J Intern Med 30(3):362–371. https://doi.org/10.3904/kjim.2015.30.3.362

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kim YR, Kim SJ, Cheong JW, Yang DH, Lee H, Eom HS, Sung YO, Kim HJ, Kang HJ, Lee WS, Park Y, Yang WI, Min YH, Kim JS (2016) The different roles of molecular classification according to upfront autologous stem cell transplantation in advanced-stage diffuse large B cell lymphoma patients with elevated serum lactate dehydrogenase. Ann Hematol 95(9):1491–1501. https://doi.org/10.1007/s00277-016-2729-4

    Article  PubMed  Google Scholar 

  17. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:d5928. https://doi.org/10.1136/bmj.d5928

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lo CK, Mertz D, Loeb M (2014) Newcastle-Ottawa scale: comparing reviewers’ to authors’ assessments. BMC Med Res Methodol 14:45. https://doi.org/10.1186/1471-2288-14-45

    Article  PubMed  PubMed Central  Google Scholar 

  19. Cook DA, Reed DA (2015) Appraising the quality of medical education research methods: the medical education research study quality instrument and the Newcastle-Ottawa scale-education. Acad Med 90(8):1067–1076. https://doi.org/10.1097/acm.0000000000000786

    Article  PubMed  Google Scholar 

  20. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR (2007) Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 8:16. https://doi.org/10.1186/1745-6215-8-16

    Article  PubMed  PubMed Central  Google Scholar 

  21. Chiappella A, Martelli M, Angelucci E, Brusamolino E, Evangelista A, Carella AM, Stelitano C, Rossi G, Balzarotti M, Merli F, Gaidano G, Pavone V, Rigacci L, Zaja F, D’Arco A, Cascavilla N, Russo E, Castellino A, Gotti M, Congiu AG, Cabras MG, Tucci A, Agostinelli C, Ciccone G, Pileri SA, Vitolo U (2017) 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):1076–1088. https://doi.org/10.1016/s1470-2045(17)30444-8

    Article  PubMed  Google Scholar 

  22. Schmitz N, Nickelsen M, Ziepert M, Haenel M, Borchmann P, Schmidt C, Viardot A, Bentz M, Peter N, Ehninger G, Doelken G, Ruebe C, Truemper L, Rosenwald A, Pfreundschuh M, Loeffler M, Glass B (2012) 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):1250–1259. https://doi.org/10.1016/s1470-2045(12)70481-3

    Article  PubMed  Google Scholar 

  23. Shin HJ, Yoon DH, Lee HS, Oh SY, Yang DH, Kang HJ, Chong SY, Park Y, Do Y, Lim SN, Jo JC, Lee WS, Chung JS (2016) Induction chemotherapy followed by up-front autologous stem cell transplantation may have a survival benefit in high-risk diffuse large B-cell lymphoma patients. Exp Hematol 44(1):3–13. https://doi.org/10.1016/j.exphem.2015.08.008

    Article  PubMed  Google Scholar 

  24. Nakaya A, Fujita S, Satake A, Nakanishi T, Azuma Y, Tsubokura Y, Hotta M, Yoshimura H, Ishii K, Ito T, Nomura S (2017) Upfront high-dose chemotherapy combined with autologous stem cell transplantation: potential survival benefit for patients with high-risk diffuse large B-cell lymphoma. Oncol Lett 14(3):3803–3808. https://doi.org/10.3892/ol.2017.6589

    Article  PubMed  PubMed Central  Google Scholar 

  25. Wang X, Xia B, Wang CY, Li MZ, Xu W, Yuan T, Tian C, Zhao HF, Yang HL, Zhao ZG, Wang XF, Wang YF, Yu Y, Zhang YZ (2019) A comparative study of induction chemotherapy with or without autologous hematopoietic stem cell transplantation in the treatment of newly diagnosed young medium/high risk diffuse large B cell lymphoma patients. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 40(2):117–124. https://doi.org/10.3760/cma.j.issn.0253-2727.2019.02.005

    Article  PubMed  Google Scholar 

  26. Zhao Y, Wang H, Jin S, Zheng J, Huang M, Tang Y, Jin Z, Qiu H, Tang X, Fu C, Han Y, Wu DP (2017) Prognostic analysis of DLBCL patients and the role of upfront ASCT in high-intermediate and high-risk patients. Oncotarget 8(42):73168–73176. https://doi.org/10.18632/oncotarget.17324

    Article  PubMed  PubMed Central  Google Scholar 

  27. Cortelazzo S, Tarella C, Gianni AM, Ladetto M, Barbui AM, Rossi A, Gritti G, Corradini P, Di Nicola M, Patti C, Mule A, Zanni M, Zoli V, Billio A, Piccin A, Negri G, Castellino C, Di Raimondo F, Ferreri AJ, Benedetti F, La Nasa G, Gini G, Trentin L, Frezzato M, Flenghi L, Falorio S, Chilosi M, Bruna R, Tabanelli V, Pileri S, Masciulli A, Delaini F, Boschini C, Rambaldi A (2016) Randomized trial comparing R-CHOP versus high-dose sequential chemotherapy in high-risk patients with diffuse large B-cell lymphomas. J Clin Oncol Off J Am Soc Clin Oncol 34(33):4015–4022. https://doi.org/10.1200/jco.2016.67.2980

    Article  Google Scholar 

  28. Nagle SJ, Woo K, Schuster SJ, Nasta SD, Stadtmauer E, Mick R, Svoboda J (2013) Outcomes of patients with relapsed/refractory diffuse large B-cell lymphoma with progression of lymphoma after autologous stem cell transplantation in the rituximab era. Am J Hematol 88(10):890–894. https://doi.org/10.1002/ajh.23524

    Article  PubMed  Google Scholar 

  29. Zhang X, Fan W, Xia ZJ, Hu YY, Lin XP, Zhang YR, Li ZM, Liang PY, Li YH (2015) Use of subsequent PET/CT in diffuse large B-cell lymphoma patients in complete remission following primary therapy. Chin J Cancer 34(2):70–78. https://doi.org/10.5732/cjc.014.10124

    Article  PubMed  PubMed Central  Google Scholar 

  30. Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, Roulland S, Kasbekar M, Young RM, Shaffer AL, Hodson DJ, Xiao W, Yu X, Yang Y, Zhao H, Xu W, Liu X, Zhou B, Du W, Chan WC, Jaffe ES, Gascoyne RD, Connors JM, Campo E, Lopez-Guillermo A, Rosenwald A, Ott G, Delabie J, Rimsza LM, Tay Kuang Wei K, Zelenetz AD, Leonard JP, Bartlett NL, Tran B, Shetty J, Zhao Y, Soppet DR, Pittaluga S, Wilson WH, Staudt LM (2018) Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med 378(15):1396–1407. https://doi.org/10.1056/NEJMoa1801445

    Article  PubMed  PubMed Central  Google Scholar 

  31. Chapuy B, Stewart C, Dunford AJ, Kim J, Kamburov A, Redd RA, Lawrence MS, Roemer MGM, Li AJ, Ziepert M, Staiger AM, Wala JA, Ducar MD, Leshchiner I, Rheinbay E, Taylor-Weiner A, Coughlin CA, Hess JM, Pedamallu CS, Livitz D, Rosebrock D, Rosenberg M, Tracy AA, Horn H, van Hummelen P, Feldman AL, Link BK, Novak AJ, Cerhan JR, Habermann TM, Siebert R, Rosenwald A, Thorner AR, Meyerson ML, Golub TR, Beroukhim R, Wulf GG, Ott G, Rodig SJ, Monti S, Neuberg DS, Loeffler M, Pfreundschuh M, Trumper L, Getz G, Shipp MA (2018) Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med 24(5):679–690. https://doi.org/10.1038/s41591-018-0016-8

    Article  PubMed  PubMed Central  Google Scholar 

  32. Zhong H, Chen J, Cheng S, Chen S, Shen R, Shi Q, Xu P, Huang H, Zhang M, Wang L, Wu D, Zhao W (2019) Prognostic nomogram incorporating inflammatory cytokines for overall survival in patients with aggressive non-Hodgkin’s lymphoma. EBioMedicine 41:167–174. https://doi.org/10.1016/j.ebiom.2019.02.048

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by grants from the National Natural Science Foundation of China (81672686, 81603137, 81973384) and Special Support Program of Sun Yat-sen University Cancer Center (PT19020401).

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  1. Shu-Yun Ma, Xiao-Peng Tian and Jun Cai contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of China

    Shu-Yun Ma, Xiao-Peng Tian, Jun Cai, Hui-Qiang Huang, Tong-Yu Lin, Zhi-Ming Li & Qing-Qing Cai

  2. Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China

    Guang-Zheng Zhong & Xu Chen

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Contributions

Study concept and design: Qing-Qing Cai, Shu-Yun Ma

Acquisition of data: Shu-Yu Ma, Xiao-Peng Tian, Jun-Cai, Guang-Zheng Zhong, Xu Chen

Analysis and interpretation of data: Shu-Yu Ma, Xiao-Peng Tian, Jun-Cai, Guang-Zheng Zhong, Xu Chen

Drafting of the manuscript: Shu-Yun Ma, Qing-Qing Cai

Critical revision of manuscript for important intellectual content: Hui-Qiang Huang, Tong-Yu Lin, Zhi-Ming Li

Statistical analysis: Shu-Yun Ma, Xiao-Peng Tian, Jun-Cai

Supervision: Qing-Qing Cai

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Correspondence to Qing-Qing Cai.

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Ma, SY., Tian, XP., Cai, J. et al. Upfront autologous stem cell transplantation for untreated diffuse large B cell lymphoma patients in rituximab era: a systematic review and meta-analysis. Ann Hematol 99, 1311–1319 (2020). https://doi.org/10.1007/s00277-020-04016-3

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