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Prediction of high risk for death in patients with follicular lymphoma receiving rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in first-line chemotherapy

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Risk stratification of patients with relapsed and refractory follicular lymphoma (FL) remains challenging. Recently, much attention has been paid to the impact of early progression of disease within 2 years of diagnosis (early POD) on subsequent survival. The aim of this study was to clarify the clinical features and prognostic factors of patients with FL who experienced early POD. Data were available for 94 patients diagnosed with FL (clinical stage II–IV) who had received immunochemotherapy. Early POD was seen in 20 % of these patients. The Cox proportional hazards model showed worse overall survival (OS) in the patients with early POD compared with those without early POD (5-year OS rates 48 % vs. 96 %, P < 0.0001). In multivariate analysis, early POD (P = 0.003) and poor performance status (P = 0.006) remained a significant factor for subsequent OS. In Follicular Lymphoma International Prognostic Index (FLIPI)- and Follicular Lymphoma International Prognostic Index-2 (FLIPI2)-adjusted Cox regression analysis, early POD was associated with markedly reduced OS with a hazard ratio of 11.2 [95 % confidence interval (CI) 3.13–40.3, P < 0.001] and 13.5 (95 % CI 3.22–56.3, P < 0.003), respectively. Among patients who had early POD, high levels of serum lactate dehydrogenase (LDH) both at the time of initial diagnosis and first progression could be associated with worse survival (2-year OS rates 33 vs. 92 %, P < 0.0001). Evaluation of LDH levels at the time of initial diagnosis and first progression may be important to define patients who were associated with worse prognosis. Risk stratification of patients with early POD could lead to improved clinical outcomes for FL patients. Further research is needed to investigate its value for decision making.

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Lactate dehydrogenase

Early POD:

Progression of disease within 2 years after initial diagnosis


  1. Lymphoma study group of Japanese pathologists (2000) (2000) The world health organization classification of malignant lymphomas in Japan incidence of recently recognized entities. Lymphoma Study Group of Japanese Pathologists. Pathol Int 50(9):696–702

    Article  Google Scholar 

  2. Ganti AK, Bociek RG, Bierman PJ, Enke CA, Vose JM, Armitage JO (2005) Follicular lymphoma: expanding therapeutic options. Oncology 19(2):213–228

    PubMed  Google Scholar 

  3. Swenson WT, Wooldridge JE, Lynch CF, Forman-Hoffman VL, Chrischilles E, Link BK (2005) Improved survival of follicular lymphoma patients in the United States. J Clin Oncol 23(22):5019–5026

    Article  PubMed  Google Scholar 

  4. Link BK, Maurer MJ, Nowakowski GS, Ansell SM, Macon WR, Syrbu SI, Slager SL, Thompson CA, Inwards DJ, Johnston PB, Colgan JP, Witzig TE, Habermann TM, Cerhan JR (2013) Rates and outcomes of follicular lymphoma transformation in the immunochemotherapy era: a report from the University of Iowa/Mayo Clinic specialized program of research excellence molecular epidemiology resource. J Clin Oncol 31(26):3272–3278

    Article  PubMed  PubMed Central  Google Scholar 

  5. Casulo C, Byrtek M, Dawson KL, Zhou X, Farber CM, Flowers CR, Hainsworth JD, Maurer MJ, Cerhan JR, Link BK, Zelenetz AD, Friedberg JW (2015) Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the national lymphocare study. J Clin Oncol 33(23):2516–2522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Buske C, Hoster E, Dreyling M, Hasford J, Unterhalt M, Hiddemann W (2006) The Follicular Lymphoma International Prognostic Index (FLIPI) separates high-risk from intermediate- or low-risk patients with advanced-stage follicular lymphoma treated front-line with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with respect to treatment outcome. Blood 108(5):1504–1508

    Article  CAS  PubMed  Google Scholar 

  7. Federico M, Luminari S, Dondi A, Tucci A, Vitolo U, Rigacci L, Di Raimondo F, Carella AM, Pulsoni A, Merli F, Arcaini L, Angrilli F, Stelitano C, Gaidano G, Dell’olio M, Marcheselli L, Franco V, Galimberti S, Sacchi S, Brugiatelli M (2013) R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol 31(12):1506–1513

    Article  CAS  PubMed  Google Scholar 

  8. Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J, Solal-Celigny P, Offner F, Walewski J, Raposo J, Jack A, Smith P (2005) CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 105(4):1417–1423

  9. Salles G, Seymour JF, Offner F, Lopez-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah R, Catalano JV, Brice P, Caballero D, Haioun C, Pedersen LM, Delmer A, Simpson D, Leppa S, Soubeyran P, Hagenbeek A, Casasnovas O, Intragumtornchai T, Ferme C, da Silva MG, Sebban C, Lister A, Estell JA, Milone G, Sonet A, Mendila M, Coiffier B, Tilly H (2011) Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 377(9759):42–51

    Article  CAS  PubMed  Google Scholar 

  10. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V, International Harmonization Project on L (2007) Revised response criteria for malignant lymphoma. J Clin Oncol 25(5):579–586

    Article  Google Scholar 

  11. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, Grillo-Lopez A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, Harris NL, Armitage JO, Carter W, Hoppe R, Canellos GP (1999) Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 17(4):1244–1253

    CAS  PubMed  Google Scholar 

  12. Solal-Celigny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R, Au WY, Bellei M, Brice P, Caballero D, Coiffier B, Conde-Garcia E, Doyen C, Federico M, Fisher RI, Garcia-Conde JF, Guglielmi C, Hagenbeek A, Haioun C, Leblanc M, Lister AT, Lopez-Guillermo A, McLaughlin P, Milpied N, Morel P, Mounier N, Proctor SJ, Rohatiner A, Smith P, Soubeyran P, Tilly H, Vitolo U, Zinzani PL, Zucca E, Montserrat E (2004) Follicular lymphoma international prognostic index. Blood 104(5):1258–1265

    Article  CAS  PubMed  Google Scholar 

  13. Federico M, Bellei M, Marcheselli L, Luminari S, Lopez-Guillermo A, Vitolo U, Pro B, Pileri S, Pulsoni A, Soubeyran P, Cortelazzo S, Martinelli G, Martelli M, Rigacci L, Arcaini L, Di Raimondo F, Merli F, Sabattini E, McLaughlin P, Solal-Celigny P (2009) Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol 27(27):4555–4562

    Article  PubMed  Google Scholar 

  14. Fleming TR, Lin DY (2000) Survival analysis in clinical trials: past developments and future directions. Biometrics 56(4):971–983

    Article  CAS  PubMed  Google Scholar 

  15. Simon R, Makuch RW (1984) A non-parametric graphical representation of the relationship between survival and the occurrence of an event: application to responder versus non-responder bias. Stat Med 3(1):35–44

    Article  CAS  PubMed  Google Scholar 

  16. Anderson JR, Cain KC, Gelber RD (2008) Analysis of survival by tumor response and other comparisons of time-to-event by outcome variables. J Clin Oncol 26(24):3913–3915

    Article  PubMed  Google Scholar 

  17. Delgado J, Pereira A, Villamor N, Lopez-Guillermo A, Rozman C (2014) Survival analysis in hematologic malignancies: recommendations for clinicians. Haematologica 99(9):1410–1420

    Article  PubMed  PubMed Central  Google Scholar 

  18. Kato H, Yamamoto K, Matsuo K, Oki Y, Taji H, Kuwatsuka Y, Seto M, Kagami Y, Morishima Y (2010) Clinical impact and predisposing factors of delayed-onset neutropenia after autologous hematopoietic stem-cell transplantation for B-cell non-Hodgkin lymphoma: association with an incremental risk of infectious events. Ann Oncol 21(8):1699–1705

    Article  CAS  PubMed  Google Scholar 

  19. Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grunhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Durk H, Ballo H, Stauch M, Roller F, Barth J, Hoelzer D, Hinke A, Brugger W, Study group indolent L (2013) Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 381 (9873):1203–1210

  20. Press OW, Unger JM, Rimsza LM, Friedberg JW, Leblanc M, Czuczman MS, Kaminski M, Braziel RM, Spier C, Gopal AK, Maloney DG, Cheson BD, Dakhil SR, Miller TP, Fisher RI (2013) Phase III randomized intergroup trial of CHOP plus rituximab compared with CHOP chemotherapy plus (131)iodine-tositumomab for previously untreated follicular non-Hodgkin lymphoma: SWOG S0016. J Clin Oncol 31(3):314–320

  21. O’Shea D, O’Riain C, Taylor C, Waters R, Carlotti E, MacDougall F, Gribben J, Rosenwald A, Ott G, Rimsza LM, Smeland EB, Johnson N, Campo E, Greiner TC, Chan WC, Gascoyne RD, Wright G, Staudt LM, Lister TA, Fitzgibbon J (2008) The presence of TP53 mutation at diagnosis of follicular lymphoma identifies a high-risk group of patients with shortened time to disease progression and poorer overall survival. Blood 112(8):3126–3129

    Article  PubMed  PubMed Central  Google Scholar 

  22. Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC, Fisher RI, Braziel RM, Rimsza LM, Grogan TM, Miller TP, Leblanc M, Greiner TC, Weisenburger DD, Lynch JC, Vose J, Armitage JO, Smeland EB, Kvaloy S, Holte H, Delabie J, Connors JM, Lansdorp PM, Ouyang Q, Lister TA, Davies AJ, Norton AJ, Muller-Hermelink HK, Ott G, Campo E, Montserrat E, Wilson WH, Jaffe ES, Simon R, Yang L, Powell J, Zhao H, Goldschmidt N, Chiorazzi M, Staudt LM (2004) Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 351(21):2159–2169

    Article  CAS  PubMed  Google Scholar 

  23. Okosun J, Bodor C, Wang J, Araf S, Yang CY, Pan C, Boller S, Cittaro D, Bozek M, Iqbal S, Matthews J, Wrench D, Marzec J, Tawana K, Popov N, O’Riain C, O’Shea D, Carlotti E, Davies A, Lawrie CH, Matolcsy A, Calaminici M, Norton A, Byers RJ, Mein C, Stupka E, Lister TA, Lenz G, Montoto S, Gribben JG, Fan Y, Grosschedl R, Chelala C, Fitzgibbon J (2014) Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet 46(2):176–181

    Article  CAS  PubMed  Google Scholar 

  24. Pastore A, Jurinovic V, Kridel R, Hoster E, Staiger AM, Szczepanowski M, Pott C, Kopp N, Murakami M, Horn H, Leich E, Moccia AA, Mottok A, Sunkavalli A, Van Hummelen P, Ducar M, Ennishi D, Shulha HP, Hother C, Connors JM, Sehn LH, Dreyling M, Neuberg D, Moller P, Feller AC, Hansmann ML, Stein H, Rosenwald A, Ott G, Klapper W, Unterhalt M, Hiddemann W, Gascoyne RD, Weinstock DM, Weigert O (2015) Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. The Lancet Oncology 16(9):1111–1122

    Article  CAS  PubMed  Google Scholar 

  25. Li YJ, Li ZM, Xia ZJ, Li S, Xia Y, Huang HQ, Huang JJ, Yi PY, Jiang WQ (2015) High APRIL but not BAFF serum levels are associated with poor outcome in patients with follicular lymphoma. Ann Hematol 94(1):79–88

    Article  CAS  PubMed  Google Scholar 

  26. Witzens-Harig M, Foa R, Di Rocco A, van Hazel G, Chamone DF, Rowe JM, Arcaini L, Poddubnaya I, Ho AD, Ivanova V, Vranovsky A, Thurley D, Oertel S (2014) Maintenance with rituximab is safe and not associated with severe or uncommon infections in patients with follicular lymphoma: results from the phase IIIb MAXIMA study. Ann Hematol 93(10):1717–1724

    Article  CAS  PubMed  Google Scholar 

  27. Ghielmini M, Vitolo U, Kimby E, Montoto S, Walewski J, Pfreundschuh M, Federico M, Hoskin P, McNamara C, Caligaris-Cappio F, Stilgenbauer S, Marcus R, Trneny M, Dreger P, Montserrat E, Dreyling M, Panel Members of the 1st ECCoML (2013) ESMO guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). Ann Oncol 24(3):561–576

  28. Montoto S, Corradini P, Dreyling M, Ghielmini M, Kimby E, Lopez-Guillermo A, Mackinnon S, Marcus RE, Salles G, Schouten HC, Sureda A, Dreger P (2013) Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT-Lymphoma Working Party. Haematologica 98(7):1014–1021

    Article  PubMed  PubMed Central  Google Scholar 

  29. Conconi A, Franceschetti S, Aprile Von Hohenstaufen K, Margiotta-Casaluci G, Stathis A, Moccia AA, Bertoni F, Ramponi A, Mazzucchelli L, Cavalli F, Gaidano G, Zucca E (2015) Histologic transformation in marginal zone lymphomas. Ann Oncol 26(11):2329–2335

    Article  CAS  PubMed  Google Scholar 

  30. Casulo C, Burack WR, Friedberg JW (2015) Transformed follicular non-Hodgkin lymphoma. Blood 125(1):40–47

    Article  CAS  PubMed  Google Scholar 

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The authors would like to thank all the doctors and nurses for their excellent patient care. We would also like to thank Yasutaka Okada, Mako Hagino, and the clinical research staff for their technical assistance and Yuka Owaki for her excellent secretarial assistance. This work was supported in part by the National Cancer Center Research and Development Fund (26-A-4).

Author contributions

S.M. collected and interpreted the data and contributed to the discussion; H.K. designed the study, collected, analyzed and interpreted the data, and wrote the manuscript; Y.H. collected the data and contributed to the discussion; H.Y., T.S., and H.T. contributed to the discussion; Y.Y. and S.N. were responsible for pathological discussion and interpreted the data; and K.Y. and T.K. supervised the research.

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Correspondence to Tomohiro Kinoshita.

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Compliance with ethical standards

Approval for this study was obtained from the Institutional Review Board at Aichi Cancer Center. This study was conducted in accordance with the Declaration of Helsinki.

Conflict of interests

T.K. has received research funding from Zenyaku Kogyo, Chugai, Ono, and Takeda. K.Y. has received funding from ARIAD, AbbVie, and Pfizer. The other authors did not receive financial compensation for authoring the manuscript.

Additional information

Satsuki Murakami and Harumi Kato equally contributed to this study.

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Murakami, S., Kato, H., Higuchi, Y. et al. Prediction of high risk for death in patients with follicular lymphoma receiving rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in first-line chemotherapy. Ann Hematol 95, 1259–1269 (2016).

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