Prophylactic modified donor lymphocyte infusion after low-dose ATG-F-based haploidentical HSCT with myeloablative conditioning in high-risk acute leukemia: a matched-pair analysis

Abstract

Both haploidentical hematopoietic stem cell transplantation (HSCT) and donor lymphocyte infusion (DLI) exhibit strong graft-versus-leukemia (GVL) effect. However, the role of prophylactic DLI following haploidentical HSCT remains unclear. Here, 34 patients with high-risk acute leukemia who underwent low-dose anti-T-lymphocyte globulin-Fresenius (ATG-F)-based myeloablative haploidentical HSCT and prophylactic modified DLI (pro-DLI) were well-matched with patients without pro-DLI. The 5-year overall survival (OS) (67.8% versus 41.3%, P < 0.01) and leukemia-free survival (LFS) (64.6% versus 33.9%, P < 0.01) of pro-DLI cohort were superior to the control cohort. A slightly higher GVHD-free/relapse-free survival was found in the pro-DLI cohort (32.8% versus 16.3%, P = 0.32). The 5-year cumulative incidence of relapse of the pro-DLI recipients was significantly lower than that of the control cohort (14.7% versus 49.3%, P = 0.01). The cumulative incidence of grades II-IV and III-IV acute GVHD at 100 days after pro-DLI was 17.6% and 9.1%, respectively. There was no difference between the two cohorts in terms of the cumulative incidence of chronic GVHD and non-relapse mortality. Data from the multivariate analysis demonstrated that pro-DLI was an independent protective variable for LFS (P = 0.01, hazard ratio {HR} = 0.35), OS (P = 0.01, HR = 0.32), and relapse (P = 0.02, HR = 0.33). Taken together, we demonstrate that pro-DLI after ATG-F-based HSCT effectively decreases the risk of relapse and improves long-term survival of patients with high-risk acute leukemia without increasing treatment toxicity.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Diagram of prophylactic modified donor lymphocyte infusion and matched-pair analysis.
Fig. 2: Cumulative incidence of GVHD.
Fig. 3: Cumulative incidence of relapse and NRM.
Fig. 4: Survival.

References

  1. 1.

    Mielcarek M, Storer BE, Flowers ME, Storb R, Sandmaier BM, Martin PJ. Outcomes among patients with recurrent high-risk hematologic malignancies after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transpl. 2007;13:1160–8.

    Article  Google Scholar 

  2. 2.

    Brissot E, Labopin M, Ehninger G, Stelljes M, Brecht A, Ganser A, et al. Haploidentical versus unrelated allogeneic stem cell transplantation for relapsed/refractory acute myeloid leukemia: a report on 1578 patients from the Acute Leukemia Working Party of the EBMT. Haematologica. 2019;104:524–32.

    CAS  Article  Google Scholar 

  3. 3.

    Tachibana T, Kanda J, Ishizaki T, Najima Y, Tanaka M, Doki N et al. Outcomes and prognostic factors for patients with relapsed or refractory acute lymphoblastic leukemia who underwent allogeneic hematopoietic cell transplantation: a KSGCT multicenter analysis. Biol Blood Marrow Transpl. 2020; e-pub ahead of print 18 January 2020; https://doi.org/10.1016/j.bbmt.2020.01.007.

  4. 4.

    Luo Y, Xiao HW, Lai XY, Shi JM, Tan YM, He JS, et al. T-cell-replete haploidentical HSCT with low-dose anti-T-lymphocyte globulin compared with matched sibling HSCT and unrelated HSCT. Blood. 2014;124:2735–43.

    CAS  Article  Google Scholar 

  5. 5.

    Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W. Donor lymphocyte infusion for the treatment of leukemia relapse after HLA-mismatched/haploidentical T-cell-replete hematopoietic stem cell transplantation. Haematologica. 2007;92:414–7.

    Article  Google Scholar 

  6. 6.

    Takami A, Yano S, Yokoyama H, Kuwatsuka Y, Yamaguchi T, Kanda Y, et al. Donor lymphocyte infusion for the treatment of relapsed acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation: a retrospective analysis by the Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation. Biol Blood Marrow Transpl. 2014;20:1785–90.

    Article  Google Scholar 

  7. 7.

    Zeidan AM, Forde PM, Symons H, Chen A, Smith BD, Pratz K, et al. HLA-haploidentical donor lymphocyte infusions for patients with relapsed hematologic malignancies after related HLA-haploidentical bone marrow transplantation. Biol Blood Marrow Transpl. 2014;20:314–8.

    CAS  Article  Google Scholar 

  8. 8.

    Miyamoto T, Fukuda T, Nakashima M, Henzan T, Kusakabe S, Kobayashi N, et al. Donor Lymphocyte Infusion for Relapsed Hematological Malignancies after Unrelated Allogeneic Bone Marrow Transplantation Facilitated by the Japan Marrow Donor Program. Biol Blood Marrow Transpl. 2017;23:938–44.

    Article  Google Scholar 

  9. 9.

    Gao XN, Lin J, Wang SH, Huang WR, Li F, Li HH, et al. Donor lymphocyte infusion for prevention of relapse after unmanipulated haploidentical PBSCT for very high-risk hematologic malignancies. Ann Hematol. 2019;98:185–93.

    CAS  Article  Google Scholar 

  10. 10.

    Gilman AL, Leung W, Cowan MJ, Cannon M, Epstein S, Barnhart C, et al. Donor lymphocyte infusion and methotrexate for immune recovery after T-cell depleted haploidentical transplantation. Am J Hematol. 2018;93:169–78.

    CAS  Article  Google Scholar 

  11. 11.

    Wang Y, Liu DH, Xu LP, Liu KY, Chen H, Zhang XH, et al. Prevention of relapse using granulocyte CSF-primed PBPCs following HLA-mismatched/haploidentical, T-cell-replete hematopoietic SCT in patients with advanced-stage acute leukemia: a retrospective risk-factor analysis. Bone Marrow Transpl. 2012;47:1099–104.

    CAS  Article  Google Scholar 

  12. 12.

    Cauchois R, Castagna L, Pagliardini T, Harbi S, Calmels B, Bramanti S, et al. Prophylactic donor lymphocyte infusions after haploidentical haematopoietic stem cell transplantation for high risk haematological malignancies: a retrospective bicentric analysis of serial infusions of increasing doses of CD3(+) cells. Br J Haematol 2019;185:570–3.

    Article  Google Scholar 

  13. 13.

    Dholaria B, Savani BN, Labopin M, Luznik L, Ruggeri A, Mielke S, et al. Clinical applications of donor lymphocyte infusion from an HLA-haploidentical donor: consensus recommendations from the Acute Leukemia Working Party of the EBMT. Haematologica. 2020;105:47–58.

    CAS  Article  Google Scholar 

  14. 14.

    Weisdorf DJ, Millard HR, Horowitz MM, Hyare PS, Champlin R, Ho V, et al. Allogeneic transplantation for advanced acute myeloid leukemia: the value of complete remission. Cancer. 2017;123:2025–34.

    CAS  Article  Google Scholar 

  15. 15.

    Middeke JM, Herold S, Rucker-Braun E, Berdel WE, Stelljes M, Kaufmann M, et al. TP53 mutation in patients with high-risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation. Br J Haematol 2016;172:914–22.

    CAS  Article  Google Scholar 

  16. 16.

    Zhou Y, Othus M, Araki D, Wood BL, Radich JP, Halpern AB, et al. Pre- and post-transplant quantification of measurable (‘minimal’) residual disease via multiparameter flow cytometry in adult acute myeloid leukemia. Leukemia. 2016;30:1456–64.

    CAS  Article  Google Scholar 

  17. 17.

    Ciurea SO, Labopin M, Socie G, Volin L, Passweg J, Chevallier P, et al. Relapse and survival after transplantation for complex karyotype acute myeloid leukemia: A report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation and the University of Texas MD Anderson Cancer Center. Cancer. 2018;124:2134–41.

    CAS  Article  Google Scholar 

  18. 18.

    Schuurhuis GJ, Heuser M, Freeman S, Bene MC, Buccisano F, Cloos J, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018;131:1275–91.

    CAS  Article  Google Scholar 

  19. 19.

    Bruggemann M, Kotrova M. Minimal residual disease in adult ALL: technical aspects and implications for correct clinical interpretation. Blood Adv. 2017;1:2456–66.

    Article  Google Scholar 

  20. 20.

    Wang Y, Chen H, Chen J, Han M, Hu J, Jiong H, et al. The consensus on the monitoring, treatment, and prevention of leukemia relapse after allogeneic hematopoietic stem cell transplantation in China. Cancer Lett 2018;438:63–75.

    CAS  Article  Google Scholar 

  21. 21.

    Holtan SG, DeFor TE, Lazaryan A, Bejanyan N, Arora M, Brunstein CG, et al. Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation. Blood. 2015;125:1333–8.

    CAS  Article  Google Scholar 

  22. 22.

    Scrucca L, Santucci A, Aversa F. Competing risk analysis using R: an easy guide for clinicians. Bone Marrow Transpl. 2007;40:381–7.

    CAS  Article  Google Scholar 

  23. 23.

    Schroeder T, Czibere A, Platzbecker U, Bug G, Uharek L, Luft T, et al. Azacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation. Leukemia. 2013;27:1229–35.

    CAS  Article  Google Scholar 

  24. 24.

    Rodrigues CA, Sanz G, Brunstein CG, Sanz J, Wagner JE, Renaud M, et al. Analysis of risk factors for outcomes after unrelated cord blood transplantation in adults with lymphoid malignancies: a study by the Eurocord-Netcord and lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol 2009;27:256–63.

    Article  Google Scholar 

  25. 25.

    Wang Y, Liu DH, Fan ZP, Sun J, Wu XJ, Ma X, et al. Prevention of relapse using DLI can increase survival following HLA-identical transplantation in patients with advanced-stage acute leukemia: a multi-center study. Clin Transplant 2012;26:635–43.

    Article  Google Scholar 

  26. 26.

    Eefting M, Halkes CJ, de Wreede LC, van Pelt CM, Kersting S, Marijt EW, et al. Myeloablative T cell-depleted alloSCT with early sequential prophylactic donor lymphocyte infusion is an efficient and safe post-remission treatment for adult ALL. Bone Marrow Transpl. 2014;49:287–91.

    CAS  Article  Google Scholar 

  27. 27.

    Legrand F, Le Floch AC, Granata A, Furst S, Faucher C, Lemarie C, et al. Prophylactic donor lymphocyte infusion after allogeneic stem cell transplantation for high-risk AML. Bone Marrow Transpl. 2017;52:620–1.

    CAS  Article  Google Scholar 

  28. 28.

    Yan CH, Liu QF, Wu DP, Zhang X, Xu LP, Zhang XH, et al. Prophylactic Donor Lymphocyte Infusion (DLI) Followed by Minimal Residual Disease and Graft-versus-Host Disease-Guided Multiple DLIs Could Improve Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Refractory/Relapsed Acute Leukemia. Biol Blood Marrow Transpl. 2017;23:1311–9.

    Article  Google Scholar 

  29. 29.

    Schmid C, Labopin M, Schaap N, Veelken H, Schleuning M, Stadler M, et al. Prophylactic donor lymphocyte infusion after allogeneic stem cell transplantation in acute leukaemia - a matched pair analysis by the Acute Leukaemia Working Party of EBMT. Br J Haematol 2019;184:782–7.

    CAS  Article  Google Scholar 

  30. 30.

    Jaiswal SR, Zaman S, Chakrabarti A, Sen S, Mukherjee S, Bhargava S, et al. Improved Outcome of Refractory/Relapsed Acute Myeloid Leukemia after Post-Transplantation Cyclophosphamide-Based Haploidentical Transplantation with Myeloablative Conditioning and Early Prophylactic Granulocyte Colony-Stimulating Factor-Mobilized Donor Lymphocyte Infusions. Biol Blood Marrow Transpl. 2016;22:1867–73.

    CAS  Article  Google Scholar 

  31. 31.

    Huang XJ, Guo NL, Ren HY, Zhang YC, Gao ZY, Lu DP. An improved anti-leukemic effect achieved with donor progenitor cell infusion for relapse patients after allogeneic bone marrow transplantation. Chin Med J-Peking. 2003;116:736–41.

    Google Scholar 

  32. 32.

    Jedlickova Z, Schmid C, Koenecke C, Hertenstein B, Baurmann H, Schwerdtfeger R, et al. Long-term results of adjuvant donor lymphocyte transfusion in AML after allogeneic stem cell transplantation. Bone Marrow Transpl. 2016;51:663–7.

    CAS  Article  Google Scholar 

  33. 33.

    Liga M, Triantafyllou E, Tiniakou M, Lambropoulou P, Karakantza M, Zoumbos NC, et al. High alloreactivity of low-dose prophylactic donor lymphocyte infusion in patients with acute leukemia undergoing allogeneic hematopoietic cell transplantation with an alemtuzumab-containing conditioning regimen. Biol Blood Marrow Transpl. 2013;19:75–81.

    CAS  Article  Google Scholar 

  34. 34.

    Bar M, Sandmaier BM, Inamoto Y, Bruno B, Hari P, Chauncey T, et al. Donor lymphocyte infusion for relapsed hematological malignancies after allogeneic hematopoietic cell transplantation: prognostic relevance of the initial CD3+ T cell dose. Biol Blood Marrow Transpl. 2013;19:949–57.

    Article  Google Scholar 

  35. 35.

    Dazzi F, Szydlo RM, Craddock C, Cross NC, Kaeda J, Chase A, et al. Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood. 2000;95:67–71.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from The National Key Research and Development Program of China [grant number 2018YFA0107804], The National Natural Science Foundation of China [grant numbers 81970158] and Zhejiang Natural Science Foundation [grant numbers LY18H080001].

Author information

Affiliations

Authors

Corresponding authors

Correspondence to He Huang or Yi Luo.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yang, L., Tan, Y., Shi, J. et al. Prophylactic modified donor lymphocyte infusion after low-dose ATG-F-based haploidentical HSCT with myeloablative conditioning in high-risk acute leukemia: a matched-pair analysis. Bone Marrow Transplant (2020). https://doi.org/10.1038/s41409-020-01088-7

Download citation

Search