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Lymphoma

Long-term survival outcomes of reduced-intensity allogeneic or autologous transplantation in relapsed grade 3 follicular lymphoma

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Abstract

Grade 3 follicular lymphoma (FL) has aggressive clinical behavior. To evaluate the optimal first transplantation approach in relapsed/refractory grade 3 FL patients, we compared the long-term outcomes after allogeneic (allo-) vs autologous hematopoietic cell transplantation (auto-HCT) in the rituximab era. A total of 197 patients undergoing first reduced-intensity conditioning (RIC) allo-HCT or first auto-HCT during 2000–2012 were included. Rituximab-naive patients were excluded. Allo-HCT recipients were younger, more heavily pretreated and had a longer interval between diagnosis and HCT. The 5-year probabilities of non-relapse mortality (NRM), relapse/progression, PFS and overall survival (OS) for auto-HCT vs allo-HCT groups were 4% vs 27% (P<0.001), 61% vs 20% (P<0.001), 36% vs 51% (P=0.07) and 59% vs 54% (P=0.7), respectively. On multivariate analysis, auto-HCT was associated with reduced risk of NRM (relative risk (RR)=0.20; P=0.001). Within the first 11 months post HCT, auto- and allo-HCT had similar risks of relapse/progression and PFS. Beyond 11 months, auto-HCT was associated with higher risk of relapse/progression (RR=21.3; P=0.003) and inferior PFS (RR=3.2; P=0.005). In the first 24 months post HCT, auto-HCT was associated with improved OS (RR=0.42; P=0.005), but in long-time survivors (beyond 24 months) it was associated with inferior OS (RR=3.6; P=0.04). RIC allo-HCT as the first transplant approach can provide improved PFS and OS, in long-term survivors.

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References

  1. Nathwani BN, Harris NL, Weisenberger DD Follicular lymphoma. In: Jaffe ES, Harris NL, Stein H, Vardiman JW (eds). World Health Organization Classification of Tumours. Pathology & Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon, France, 2008, pp 162–167.

    Google Scholar 

  2. Bilalovic N, Blystad AK, Golouh R, Nesland JM, Selak I, Trinh D et al. Expression of bcl-6 and CD10 protein is associated with longer overall survival and time to treatment failure in follicular lymphoma. Am J Clin Pathol 2004; 121: 34–42.

    Article  Google Scholar 

  3. Pruneri G, Valentini S, Fabris S, Del Curto B, Laszlo D, Bertolini F et al. Cyclin D3 immunoreactivity in follicular lymphoma is independent of the t(6;14)(p21.1;q32.3) translocation or cyclin D3 gene amplification and is correlated with histologic grade and Ki-67 labeling index. Int J Cancer 2004; 112: 71–77.

    CAS  Article  Google Scholar 

  4. Guo Y, Karube K, Kawano R, Kawano R, Yamaguchi T, Suzumiya J et al. Low-grade follicular lymphoma with t(14;18) presents a homogeneous disease entity otherwise the rest comprises minor groups of heterogeneous disease entities with Bcl2 amplification, Bcl6 translocation or other gene aberrances. Leukemia 2005; 19: 1058–1063.

    CAS  Article  Google Scholar 

  5. Naresh KN . MUM1 expression dichotomises follicular lymphoma into predominantly, MUM1-negative low-grade and MUM1-positive high-grade subtypes. Haematologica 2007; 92: 267–268.

    Article  Google Scholar 

  6. Horn H, Schmelter C, Leich E, Salaverria I, Katzenberger T, Ott MM et al. Follicular lymphoma grade 3B is a distinct neoplasm according to cytogenetic and immunohistochemical profiles. Haematologica 2011; 96: 1327–1334.

    Article  Google Scholar 

  7. Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005; 106: 3725–3732.

    CAS  Article  Google Scholar 

  8. Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005; 105: 1417–1423.

    CAS  Article  Google Scholar 

  9. Zelenetz AD, Gordon LI, Wierda WG, Abramson JS, Advani RH, Andreadis CB et al. Non-Hodgkin's lymphomas, version 2.2014. J Natl Compr Canc Netw 2014; 12: 916–946.

    CAS  Article  Google Scholar 

  10. Dreyling M, Ghielmini M, Marcus R, Salles G, Vitolo U, Ladetto M et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014; 25: iii76–iii82.

    Article  Google Scholar 

  11. Montoto S, Canals C, Rohatiner AZ, Taghipour G, Sureda A, Schmitz N et al. Long-term follow-up of high-dose treatment with autologous haematopoietic progenitor cell support in 693 patients with follicular lymphoma: an EBMT registry study. Leukemia 2007; 21: 2324–2331.

    CAS  Article  Google Scholar 

  12. Khouri IF, McLaughlin P, Saliba RM, Hosing C, Korbling M, Lee MS et al. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood 2008; 111: 5530–5536.

    CAS  Article  Google Scholar 

  13. Pham RN, Gooley TA, Keeney GE, Press OW, Pagel JM, Greisman HA et al. The impact of histologic grade on the outcome of high-dose therapy and autologous stem cell transplantation for follicular lymphoma. Bone Marrow Transplant 2007; 40: 1039–1044.

    CAS  Article  Google Scholar 

  14. Vose JM, Bierman PJ, Loberiza FR, Lynch JC, Bociek GR, Weisenburger DD et al. Long-term outcomes of autologous stem cell transplantation for follicular non-Hodgkin lymphoma: effect of histological grade and Follicular International Prognostic Index. Biol Blood Marrow Transplant 2008; 14: 36–42.

    Article  Google Scholar 

  15. Hamadani M, Saber W, Ahn KW, Carreras J, Cairo MS, Fenske TS et al. Impact of pretransplantation conditioning regimens on outcomes of allogeneic transplantation for chemotherapy-unresponsive diffuse large B cell lymphoma and grade III follicular lymphoma. Biol Blood Marrow Transplant 2013; 19: 746–753.

    Article  Google Scholar 

  16. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 2009; 15: 1628–1633.

    Article  Google Scholar 

  17. Weisdorf D, Spellman S, Haagenson M, Horowitz M, Lee S, Anasetti C et al. Classification of HLA-matching for retrospective analysis of unrelated donor transplantation: revised definitions to predict survival. Biol Blood Marrow Transplant 2008; 14: 748–758.

    Article  Google Scholar 

  18. Rezvani AR, Maloney DG . Rituximab resistance. Best Pract Res Clin Haematol 2011; 24: 203–216.

    CAS  Article  Google Scholar 

  19. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825–828.

    CAS  Google Scholar 

  20. Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980; 69: 204–217.

    CAS  Article  Google Scholar 

  21. Zhang X, Loberiza FR, Klein JP, Zhang MJ . A SAS macro for estimation of direct adjusted survival curves based on a stratified Cox regression model. Comput Methods Programs Biomed 2007; 88: 95–101.

    Article  Google Scholar 

  22. Zhang X, Zhang MJ . SAS macros for estimation of direct adjusted cumulative incidence curves under proportional subdistribution hazards models. Comput Methods Programs Biomed 2011; 101: 87–93.

    Article  Google Scholar 

  23. Robinson SP, Canals C, Luang JJ, Tilly H, Crawley C, Cahn JY et al. The outcome of reduced intensity allogeneic stem cell transplantation and autologous stem cell transplantation when performed as a first transplant strategy in relapsed follicular lymphoma: an analysis from the Lymphoma Working Party of the EBMT. Bone Marrow Transplant 2013; 48: 1409–1414.

    CAS  Article  Google Scholar 

  24. Wahlin BE, Yri OE, Kimby E, Holte H, Delabie J, Smeland EB et al. Clinical significance of the WHO grades of follicular lymphoma in a population-based cohort of 505 patients with long follow-up times. Br J Haematol 2012; 156: 225–233.

    Article  Google Scholar 

  25. Chau I, Jones R, Cunningham D, Wotherspoon A, Maisey N, Norman AR et al. Outcome of follicular lymphoma grade 3: is anthracycline necessary as front-line therapy? Br J Cancer 2003; 89: 36–42.

    CAS  Article  Google Scholar 

  26. Hsi ED, Mirza I, Lozanski G, Hill J, Pohlman B, Karafa MT et al. A clinicopathologic evaluation of follicular lymphoma grade 3A versus grade 3B reveals no survival differences. Arch Pathol Lab Med 2004; 128: 863–868.

    PubMed  Google Scholar 

  27. Hans CP, Weisenburger DD, Vose JM, Hock LM, Lynch JC, Aoun P et al. A significant diffuse component predicts for inferior survival in grade 3 follicular lymphoma, but cytologic subtypes do not predict survival. Blood 2003; 101: 2363–2367.

    CAS  Article  Google Scholar 

  28. Shustik J, Quinn M, Connors JM, Gascoyne RD, Skinnider B, Sehn LH . Follicular non-Hodgkin lymphoma grades 3A and 3B have a similar outcome and appear incurable with anthracycline-based therapy. Ann Oncol 2011; 22: 1164–1169.

    CAS  Article  Google Scholar 

  29. Branson K, Chopra R, Kottaridis PD, McQuaker G, Parker A, Schey S et al. Role of non-myeloablative allogeneic stem-cell transplantation after failure of autologous transplantation in patients with lymphoproliferative malignancies. J Clin Oncol 2002; 20: 4022–4031.

    Article  Google Scholar 

  30. Hosing C, Saliba RM, McLaughlin P, Andersson B, Rodriguez MA, Fayad L et al. Long-term results favor allogeneic over autologous hematopoietic stem cell transplantation in patients with refractory or recurrent indolent non-Hodgkin's lymphoma. Ann Oncol 2003; 14: 737–744.

    CAS  Article  Google Scholar 

  31. van Besien K, Loberiza FR Jr, Bajorunaite R, Armitage JO, Bashey A, Burns LJ et al. Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood 2003; 102: 3521–3529.

    CAS  Article  Google Scholar 

  32. van Besien KW, de Lima M, Giralt SA, Moore DF Jr., Khouri IF, Rondon G et al. Management of lymphoma recurrence after allogeneic transplantation: the relevance of graft-versus-lymphoma effect. Bone Marrow Transplant 1997; 19: 977–982.

    CAS  Article  Google Scholar 

  33. Mandigers CM, Verdonck LF, Meijerink JP, Dekker AW, Schattenberg AV, Raemaekers JM . Graft-versus-lymphoma effect of donor lymphocyte infusion in indolent lymphomas relapsed after allogeneic stem cell transplantation. Bone Marrow Transplant 2003; 32: 1159–1163.

    CAS  Article  Google Scholar 

  34. Lenz G, Dreyling M, Schiegnitz E, Forstpointner R, Wandt H, Freund M et al. Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood 2004; 104: 2667–2674.

    CAS  Article  Google Scholar 

  35. Sebban C, Mounier N, Brousse N, Belanger C, Brice P, Haioun C et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood 2006; 108: 2540–2544.

    CAS  Article  Google Scholar 

  36. Gyan E, Foussard C, Bertrand P, Michenet P, le Gouill S, Berthou C et al. High-dose therapy followed by autologous purged stem cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS with final results after a median follow-up of 9 years. Blood 2009; 113: 995–1001.

    CAS  Article  Google Scholar 

  37. Leisenring W, Friedman DL, Flowers ME, Schwartz JL, Deeg HJ . Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation. J Clin Oncol 2006; 24: 1119–1126.

    Article  Google Scholar 

  38. Rizzo JD, Curtis RE, Socie G, Sobocinski KA, Gilbert E, Landgren O et al. Solid cancers after allogeneic hematopoietic cell transplantation. Blood 2009; 113: 1175–1183.

    CAS  Article  Google Scholar 

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Acknowledgements

We would like to acknowledge the following working committee members for their contributions to the manuscript: Mahmoud D Aljurf, Siddhartha Ganguly, Mark S Hertzberg, Leona A Holmberg, Andreas Klein, Taiga Nishihori, Richard F Olsson and Nishitha M Reddy. Also, Maggie Simaytis for administrative assistance. The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U10HL069294 from NHLBI and NCI; a Contract No. HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); two grants (N00014-13-1-0039 and N00014-14-1-0028) from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; Allos Therapeutics Inc.; *Amgen Inc.; Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; Chimerix Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America Inc.; *Gamida Cell Teva Joint Venture Ltd; Genentech Inc.;*Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research Inc. Roswell Park Cancer Institute; HistoGenetics Inc.; Incyte Corporation; Jeff Gordon Children’s Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co. Inc.; Millennium: The Takeda Oncology Co.; *Milliman USA Inc.; *Miltenyi Biotec Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions Inc.; Osiris Therapeutics Inc.; Otsuka America Pharmaceutical Inc.; Perkin-Elmer Inc.; *Remedy Informatics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix Inc.; St Baldrick’s Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software Inc.; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *TerumoBCT; *Teva Neuroscience Inc.; *THERAKOS Inc.; University of Minnesota; University of Utah; and *Wellpoint Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the US Government.

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Correspondence to M Hamadani.

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Presented in part as an oral presentation at the annual meetings of the American Society of Clinical Oncology, Chicago, IL, May 31, 2015.

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Klyuchnikov, E., Bacher, U., Woo Ahn, K. et al. Long-term survival outcomes of reduced-intensity allogeneic or autologous transplantation in relapsed grade 3 follicular lymphoma. Bone Marrow Transplant 51, 58–66 (2016). https://doi.org/10.1038/bmt.2015.223

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