Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Outcomes of adults with lymphoma treated with nonmyeloablative TLI-ATG and radiation boost to high risk or residual disease before allogeneic hematopoietic cell transplant

Abstract

We evaluated the impact on survival of antithymocyte globulin conditioning (TLI-ATG) with radiation (RT) boost to high risk or residual disease before allogeneic hematopoietic cell transplant (allo-HCT) for adults with lymphoma (excluding mycosis fungoides and low-grade NHL other than SLL/CLL). Of 251 evaluable patients, 36 received an RT boost within 3 months of allo-HCT at our institution from 2001 to 2016. At the time of TLI-ATG, patients who received boost vs no boost had a lower rate of CR (11% vs 47%, p = 0.0003), higher rates of bulky disease (22% vs 4%, p < 0.0001), extranodal disease (39% vs 5%, p < 0.0001), and positive PET (75% vs 28%, p < 0.00001). In the boost group, the median (range) largest axial lesion diameter was 5.2 cm (1.8–22.3). Median follow-up was 50.2 months (range: 1–196). There was no significant difference in OS, time to recurrence, or time to graft failure with vs without boost. A trend toward higher percent donor CD3+ chimerism was seen with vs without boost (p = 0.0819). The worst boost-related toxicity was grade 2 dermatitis. RT boost may help successfully mitigate the risk of high risk or clinically evident residual disease in adults with lymphoma undergoing allo-HCT.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Time-to-event outcomes.
Fig. 2: Case example.
Fig. 3: Time-to-event outcomes stratified by risk factors and boost group.
Fig. 4: Percent donor CD3+ chimerism.

Similar content being viewed by others

References

  1. Barrett J, Battiwalla M. Relapse after allogeneic stem cell transplantation. Expert Rev Hematol. 2010;3:429–41.

    PubMed  PubMed Central  Google Scholar 

  2. Robinson SP, Doldstone AH, Mackinnon S, Russell N, Ruiz de Elvira C, Taghipour G, et al. Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation. Blood. 2002;100:4310–6.

    CAS  PubMed  Google Scholar 

  3. Bachanova V, Burns LJ, Ahn KW, Carreras J, Maloney DG, Sureda A, et al. Positive pre-allogeneic hematopoietic cell transplantation (alloHCT) PET scan in patients with non-Hodgkin lymphoma (NHL) predicts higher risk of relapse but has no impact on survival. Biol Blood Marrow Transplant. 2015;21:S83–S84.

    Google Scholar 

  4. Shafer JA, Heslop HE, Brenner MK, Carrum G, Wu MF, Liu H, et al. Outcome of hematopoietic stem cell transplantation as salvage therapy for Hodgkin’s lymphoma in adolesence and young adults at a single institution. Leuk Lymphoma. 2010;51:664–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Martínez C, Canals C, Sarina B, Alessandrino EP, Karakasis D, Pulsoni A, et al. Identification of prognostic factors predicting outcome in Hodgkin’s lymphoma patients relapsing after autologous stem cell transplantation. Ann Oncol. 2013;24:2430–4.

    PubMed  Google Scholar 

  6. Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME, et al. Validation and refinement of the Disease Risk Index for allogeneic hematopoietic cell transplantation. Blood. 2014;123:3664–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Aleman BM, Raemaekers JM, Tirelli U, Bortolus R, van 't Veer MB, Lybeert MLM, et al. Involved-field radiotherapy for advanced Hodgkin’s lymphoma. N Engl J Med. 2003;348:2396–406.

    PubMed  Google Scholar 

  8. Aleman BM, Raemaekers JM, Tomiŝiĉ R, Baaijens MHA, Bortolus R, Lybeert MLM, et al. Involved-field radiotherapy for patients in partial remission after chemotherapy for advanced Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys. 2007;67:19–30.

    PubMed  Google Scholar 

  9. Borchmann P, Haverkamp H, Diehl V, Cerny T, Jana M, Ho AD, et al. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage Hodgkin’s lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol. 2011;29:4234–42.

    CAS  PubMed  Google Scholar 

  10. Johnson PW, Radford JA, Cullen MH, Sydes MR, Walewski J, Jack AS, et al. Comparison of ABVD and Alternating or hybrid multidrug regimens for the treatment of advanced Hodgkin’s lymphoma: results of the United Kingdom Lymphoma Group LY09 Trial (ISRCTN97144519). J Clin Oncol. 2005;23:9208–18.

    CAS  PubMed  Google Scholar 

  11. Engert A, Haverkamp H, Kobe C, Markova J, Renner C, Ho A, et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012;379:1791–9.

    CAS  PubMed  Google Scholar 

  12. Held G, Murawski N, Ziepert M, Fleckenstein J, Pöschel V, Bittenbring CJ, et al. Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol. 2014;32:1112–8.

    PubMed  Google Scholar 

  13. Held G, Zeynalova S, Murawski N, Ziepert M, Kempf B, Viardot A, et al. Impact of rituximab and radiotherapy on outcome of patients with aggressive B-cell lymphoma and skeletal involvement. J Clin Oncol. 2013;31:4115–22.

    CAS  PubMed  Google Scholar 

  14. Pfreundschuh M, Murawski N, Ziepert M, Hänel M, Held G, Schmitz N, et al. Radiotherapy (RT) to bulky (B) and extralymphatic (E) disease in combination with 6xR-CHOP-14 or R-CHOP-21 in young good-prognosis DLBCL patients: Results of the 2x2 randomized UNFOLDER trial of the DSHNHL/GLA. J Clin Oncol. 2018;36:7574–7574.

    Google Scholar 

  15. Lamy T, Damj 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;131:174–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Pfreundschuh M, Christofyllakis K, Altmann B, Ziepert M, Haenel M, Viardot A, et al. Radiotherapy to bulky disease PET-negative after immunochemotherapy can be spared in elderly DLBCL patients: results of a planned interim analysis of the first 187 patients with bulky disease treated in the OPTIMAL>60 study of the DSHNHL. Hematol Oncol. 2017;35:129–30.

    Google Scholar 

  17. Constine LS, Yahalom J, Ng AK, Hodgson DC, Wirth A, Milgrom SA, et al. The role of radiation therapy in patients with relapsed or refractory hodgkin lymphoma: guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys. 2018;100:1100–18.

    PubMed  Google Scholar 

  18. Ng AK, Yahalom J, Goda JS, Constine LS, Pinnix CC, Kelsey CR, et al. Role of radiation therapy in patients with relapsed/refractory diffuse large B-cell lymphoma: guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys. 2018;100:652–69.

    PubMed  Google Scholar 

  19. Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28:4184–90.

    PubMed  PubMed Central  Google Scholar 

  20. Dhakal S, Bates JE, Casulo C, Friedberg JW, Becker MW, Liesveld JL, et al. Patterns and timing of failure for diffuse large B-cell lymphoma after initial therapy in a cohort who underwent autologous bone marrow transplantation for relapse. Int J Radiat Oncol Biol Phys. 2016;96:372–8.

    PubMed  Google Scholar 

  21. Mundt AJ, Sibley G, Williams S, Hallahan D, Nautiyal J, Weichselbaum RR. Patterns of failure following high-dose chemotherapy and autologous bone marrow transplantation with involved field radiotherapy for relapsed/refractory Hodgkin’s disease. Int J Radiat Oncol Biol Phys. 1995;33:261–70.

    CAS  PubMed  Google Scholar 

  22. Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapse of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med. 1995;333:1540–5.

    CAS  PubMed  Google Scholar 

  23. Spinner MA, Kennedy VE, Tamaresis JS, Tamaresis JS, Lavori PW, Arai S, et al. Nonmyeloablative TLI-ATG conditioning for allogeneic transplantation: mature follow-up from a large single-center cohort. Blood Adv. 2019;3:2454–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Baron F, Maris MB, Sandmaier BM, Storer BE, Sorror M, Diaconescu R, et al. Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol. 2005;23:1993–2003.

    PubMed  Google Scholar 

  25. Storb R, Gyurkocza B, Storer BE, Sorror ML, Blume K, Niederwieser D, et al. Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation. J Clin Oncol. 2013;31:1530–8.

    CAS  PubMed  Google Scholar 

  26. 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;15:1628–33.

    PubMed  PubMed Central  Google Scholar 

  27. McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001;97:3390–400.

    CAS  PubMed  Google Scholar 

  28. Lowsky R, Takahashi T, Liu YP, Dejbakhsh-Jones S, Grumet FC, Shizuru JA, et al. Protective conditioning for acute graft-versus-host disease. N Engl J Med. 2005;353:1321–31.

    CAS  PubMed  Google Scholar 

  29. Kohrt HE, Turnbull BB, Heydari K, Shizuru JA, Laport GG, Miklos DB, et al. TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors. Blood. 2009;114:1099–109.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Messina G, Giaccone L, Festuccia M, Irrera G, Scortechini I, Sorasio R, et al. Multicenter experience using total lymphoid irradiation and antithymocyte globulin as conditioning for allografting in hematological malignancies. Biol Blood Marrow Transplant. 2012;18:1600–7.

    PubMed  Google Scholar 

  31. Baron F, Zachée P, Maertens J, Kerre T, Ory A, Seidel L, et al. Non-myeloablative allogeneic hematopoietic cell transplantation following fludarabine plus 2 Gy TBI or ATG plus 8 Gy TLI: a phase II randomized study from the Belgian Hematological Society. J Hematol Oncol. 2015;8:4.

    PubMed  PubMed Central  Google Scholar 

  32. Lan F, Zeng D, Higuchi M, Huie P, Higgins JP, Strober S. Predominance of NK1.1+TCR alpha beta+ or DX5+TCR alpha beta+ T cells in mice conditioned with fractionated lymphoid irradiation protects against graft-versus-host disease: “natural suppressor” cells. J Immunol. 2001;167:2087–96.

    CAS  PubMed  Google Scholar 

  33. Lan F, Zeng D, Higuchi M, Higgins JP, Strober S. Host conditioning with total lymphoid irradiation and antithymocyte globulin prevents graft-versus-host disease: the role of CD1-reactive natural killer T cells. Biol Blood Marrow Transplant. 2003;9:355–63.

    PubMed  Google Scholar 

  34. Pillai AB, George TI, Dutt S, Teo P, Strober S. Host NKT cells can prevent graft-versus-host disease and permit graft antitumor activity after bone marrow transplantation. J Immunol. 2007;178:6242–51.

    CAS  PubMed  Google Scholar 

  35. Pillai AB, George TI, Dutt S, Strober S. Host natural killer T cells induce an interleukin-4-dependent expansion of donor CD4+CD25+Foxp3+ T regulatory cells that protects against graft-versus-host disease. Blood. 2009;113:4458–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Leveson-Gower DB, Olson JA, Sega EI, Luong RH, Baker J, Zeiser R, et al. Low doses of natural killer T cells provide protection from acute graft-versus-host disease via an IL-4-dependent mechanism. Blood. 2011;117:3220–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Schneidawind D, Pierini A, Alvarez M, Pan Y, Baker J, Buechele C, et al. CD4+ invariant natural killer T cells protect from murine GVHD lethality through expansion of donor CD4+CD25+FoxP3+ regulatory T cells. Blood. 2014;124:3320–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med. 2002;196:389–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Kohrt HE, Pillai AB, Lowsky R, Strober S. NKT cells, Treg, and their interactions in bone marrow transplantation. Eur J Immunol. 2010;40:1862–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Tsai T, Goodman S, Saez R, Schiller G, Adkins D, Callander N, et al. Allogeneic bone marrow transplantation in patients who relapse after autologous transplantation. Bone Marrow Transplant. 1997;20:859–63.

    CAS  PubMed  Google Scholar 

  41. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005;106:2912–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Gauthier J, Castagna L, Garnier F, Guillaume T, Socié G, Maury S, et al. Reduced-intensity and non-myeloablative allogeneic stem cell transplantation from alternative HLA-mismatched donors for Hodgkin lymphoma: a study by the French Society of Bone Marrow Transplantation and Cellular Therapy. Bone Marrow Transplant. 2017;52:689–96.

    CAS  PubMed  Google Scholar 

  43. Schimmer AD, Jamal S, Messner H, Keating A, Meharchand J, Huebsch L, et al. Allogeneic or autologous bone marrow transplantation (BMT) for non-Hodgkin’s lymphoma (NHL): results of a provincial strategy. Bone Marrow Transplant. 2000;26:859–64.

    CAS  PubMed  Google Scholar 

  44. Nademanee A, Molina A, Dagis A, Snyder DS, O’Donnell MR, Parker P, et al. Autologous stem-cell transplantation for poor-risk and relapsed intermediate- and high-grade non-Hodgkin’s lymphoma. Clin Lymphoma. 2000;1:46–54.

    CAS  PubMed  Google Scholar 

  45. Hahn T, McCarthy PL, Carreras J, Zhang MJ, Lazarus HM, Laport GG, et al. Simplified validated prognostic model for progression-free survival after autologous transplantation for hodgkin lymphoma. Biol Blood Marrow Transplant 2013;19:1740–4. https://doi.org/10.1016/j.bbmt.2013.09.018.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Noring K, Carlsten M, Sonnevi K, and Engelbrekt Wahlin B, Johnson KB. The value of complete remission according to positron emission tomography prior to autologous stem cell transplantation in lymphoma: a population-based study showing improved outcome. BMC Cancer. 2021;21:500.

  47. Bartlett NL, Niedzwiecki D, Johnson JL, Friedberg JW, Johnson KB, van Besien K, et al. Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin’s lymphoma: CALGB 59804. Ann Oncol. 2007;18:1071–9.

    CAS  PubMed  Google Scholar 

  48. Bröckelmann PJ, Müller H, Casanovas O, Hutchings M, von Tresckow B, Jürgens M, et al. Risk factors and a prognostic score for survival after autologous stem-cell transplantation for relapsed or refractory Hodgkin lymphoma. Ann Oncol. 2017;28:1352–8.

    PubMed  Google Scholar 

  49. Rappaport AP, Lifton R, Constine LS, Abboud CN, Liesveld JL, Packman CH, et al. Autotransplantation for relapsed or refractory non-Hodgkin’s lymphoma (NHL): long-term follow-up and analysis of prognostic factors. Bone Marrow Transplant. 1997;19:883–90.

    Google Scholar 

  50. Mounier N, Gisselbrecht C, Brière J, Haioun C, Feugier P, Offner F, et al. Groupe d’Etude des Lymphomes de l’Adulte. Prognostic factors in patients with aggressive non-Hodgkin’s lymphoma treated by front-line autotransplantation after complete remission: a cohort study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 2004;22:2826–34. https://doi.org/10.1200/JCO.2004.12.032.

    Article  CAS  PubMed  Google Scholar 

  51. Illidge T, Specht L, Yahalom J, Aleman B, Kiil Berthelsen A, Constine LS, et al. Modern radiation therapy for nodal non-Hodgkin lymphoma-target definition and dose guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys. 2014;89:49–58.

    PubMed  Google Scholar 

  52. Specht L, Yahalom J, Illidge T, Kiil Berthelsen A, Constine LS, Eich HT, et al. Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group (ILROG). Int J Radiat Oncol Biol Phys. 2014;89:854–62.

    PubMed  Google Scholar 

  53. Reshef R, Hexner E, Loren A, Frey NV, Stadtmauer EA, Lungr SM, et al. Early donor chimerism levels predict relapse and survival after allogeneic stem cell transplantation with reduced-intensity conditioning. Biol Blood Marrow Transplant. 2014;20:1758–66.

    PubMed  PubMed Central  Google Scholar 

  54. Mahr B, Granofszky N, Muckenhuber M, Wekerle N. Transplantation tolerance through hematopoietic chimerism: progress and challenges for clinical translation. Front Immunol. 2017;8:1762.

    PubMed  PubMed Central  Google Scholar 

  55. Kalbasi A, June CH, Haas N, Vapiwala N. Radiation and immunotherapy: a synergistic combination. J Clin Investig. 2013;123:2756–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Chajon E, Castelli J, Marsiglia H, De Crevoisier R. The synergistic effect of radiotherapy and immunotherapy: a promising but not simple partnership. Crit Rev Oncol Hematol. 2017;111:124–32.

    PubMed  Google Scholar 

  57. Wang Y, Deng W, Li N, Neri S, Sharma A, Jiang W, et al. Combining immunotherapy and radiotherapy for cancer treatment: current challenges and future directions. Front Pharmacol. 2018;9:185.1–185.11.

    Google Scholar 

  58. Weng WK, Arai S, Rezvani A, Johnston L, Lowsky R, Miklos D, et al. Nonmyeloablative allogeneic transplantation achieves clinical and molecular remission in cutaneous T-cell lymphoma. Blood Adv. 2020;4:4474–82.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was funded in part by the National Institutes of Health, National Cancer Institute grant P01 CA049605.

Author information

Authors and Affiliations

Authors

Contributions

RTH and SMH devised the study and edited the manuscript. MLD developed the study, assisted in gathering data, and wrote the manuscript. ALJ assisted in gathering data, produced the figures, and edited the manuscript. RVE performed the analyses and edited the manuscript. MAS assisted in gathering data and edited the manuscript. RHA and RL edited the manuscript.

Corresponding author

Correspondence to R. T. Hoppe.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dworkin, M.L., Jiang, A.L., Von Eyben, R. et al. Outcomes of adults with lymphoma treated with nonmyeloablative TLI-ATG and radiation boost to high risk or residual disease before allogeneic hematopoietic cell transplant. Bone Marrow Transplant 57, 106–112 (2022). https://doi.org/10.1038/s41409-021-01495-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-021-01495-4

Search

Quick links