Skip to main content
Log in

Comparison of outcomes after donor lymphocyte infusion with or without prior chemotherapy for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

The efficacy of donor lymphocyte infusion (DLI) without chemotherapy was investigated and compared with that of chemotherapy prior to DLI (Chemo-DLI) in patients who were minimal residual disease (MRD)-positive after allogeneic hematopoietic stem cell transplantation (HSCT). We enrolled 115 consecutive patients who received either DLI (n = 20) or Chemo-DLI (n = 95) during the same period. For each DLI recipient, three recipients matched for age at the HSCT, underlying diseases, and the year of the HSCT were randomly selected from the Chemo-DLI cohort (n = 60). The 2-year cumulative incidence of severe acute graft-versus-host disease (GVHD) and chronic GVHD was comparable between the groups. Fifteen (75.0%) and 47 (78.3%) patients in the DLI and Chemo-DLI groups turned MRD-negative, respectively. The 2-year cumulative incidences of relapse and non-relapse mortality after intervention were 30.7 versus 39.6% (P = 0.582) and 10.3 versus 6.0% (P = 0.508) in the DLI and Chemo-DLI groups, respectively. The 2-year probabilities of disease-free, overall, and GVHD-free/relapse-free survival after preemptive intervention were 58.9 versus 54.3% (P = 0.862), 69.3 versus 78.1% (P = 0.361), and 44.4 versus 35.1% (P = 0.489) in the DLI and Chemo-DLI groups, respectively. In multivariate analysis, the intervention method did not significantly influence the clinical outcomes. In summary, preemptive DLI alone may be effective for patients who are MRD-positive and may be a potential alternative for patients who refuse or are unable to receive Chemo-DLI after HSCT.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Muñoz A, Badell I, Olivé T et al (2002) Second allogeneic hematopoietic stem cell transplantation in hematologic malignancies in children: long-term results of a multicenter study of the Spanish Working Party for Bone Marrow Transplantation in Children (GETMON). Haematologica 87:331–332

    PubMed  Google Scholar 

  2. Bader P, Kreyenberg H, Hoelle W et al (2004) Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem-cell transplantation: possible role for pre-emptive immunotherapy? J Clin Oncol 22:1696–1705

    Article  PubMed  Google Scholar 

  3. Horn B, Petrovic A, Wahlstrom J et al (2015) Chimerism-based pre-emptive immunotherapy with fast withdrawal of immunosuppression and donor lymphocyte infusions after allogeneic stem cell transplantation for pediatric hematologic malignancies. Biol Blood Marrow Transplant 21:729–737

    Article  PubMed  Google Scholar 

  4. Rettinger E, Willasch AM, Kreyenberg H et al (2011) Preemptive immunotherapy in childhood acute myeloid leukemia for patients showing evidence of mixed chimerism after allogeneic stem cell transplantation. Blood 118:5681–5688

    Article  CAS  PubMed  Google Scholar 

  5. Pulsipher MA (2014) Chimerism versus minimal residual disease monitoring after allogeneic transplantation—when do we act and will intervention improve outcomes? Biol Blood Marrow Transplant 20:1461–1462

    Article  PubMed  Google Scholar 

  6. Terwey TH, Hemmati PG, Nagy M et al (2014) Comparison of chimerism and minimal residual disease monitoring for relapse prediction after allogeneic stem cell transplantation for adult acute lymphoblastic leukemia. Biol Blood Marrow Transplant 20:1522–1529

    Article  PubMed  Google Scholar 

  7. Lankester AC, Bierings MB, van Wering ER et al (2010) Preemptive alloimmune intervention in high-risk pediatric acute lymphoblastic leukemia patients guided by minimal residual disease level before stem cell transplantation. Leukemia 24:1462–1469

    Article  CAS  PubMed  Google Scholar 

  8. Balduzzi A, Di Maio L, Silvestri D et al (2014) Minimal residual disease before and after transplantation for childhood acute lymphoblastic leukaemia: is there any room for intervention? Br J Haematol 164:396–408

    Article  CAS  PubMed  Google Scholar 

  9. Pulsipher MA, Langholz B, Wall DA et al (2015) Risk factors and timing of relapse after allogeneic transplantation in pediatric ALL: for whom and when should interventions be tested? Bone Marrow Transplant 50:1173–1179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mo XD, Zhang XH, Xu LP et al (2015) Interferon-α: a potentially effective treatment for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 21:1939–1947

    Article  CAS  PubMed  Google Scholar 

  11. Dominietto A, Pozzi S, Miglino M et al (2007) Donor lymphocyte infusions for the treatment of minimal residual disease in acute leukemia. Blood 109:5063–5064

    Article  CAS  PubMed  Google Scholar 

  12. Tan Y, Du K, Luo Y et al (2014) Superiority of preemptive donor lymphocyte infusion based on minimal residual disease in acute leukemia patients after allogeneic hematopoietic stem cell transplantation. Transfusion 54:1493–1500

    Article  CAS  PubMed  Google Scholar 

  13. Anguille S, Lion E, Willemen Y, Van Tendeloo VF, Berneman ZN, Smits EL (2011) Interferon-α in acute myeloid leukemia: an old drug revisited. Leukemia 25:739–748

    Article  CAS  PubMed  Google Scholar 

  14. Warlick ED, DeFor T, Blazar BR et al (2012) Successful remission rates and survival after lymphodepleting chemotherapy and donor lymphocyte infusion for relapsed hematologic malignancies post allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 18:480–486

    Article  PubMed  Google Scholar 

  15. Yan CH, Wang JZ, Liu DH et al (2013) Chemotherapy followed by modified donor lymphocyte infusion as a treatment for relapsed acute leukemia after haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion: superior outcomes compared with chemotherapy alone and an analysis of prognostic factors. Eur J Haematol 91:304–314

    Article  CAS  PubMed  Google Scholar 

  16. Yan CH, Liu DH, Liu KY et al (2012) Risk stratification-directed donor lymphocyte infusion could reduce relapse of standard-risk acute leukemia patients after allogeneic hematopoietic stem cell transplantation. Blood 119:3256–3262

    Article  CAS  PubMed  Google Scholar 

  17. He F, Warlick E, Miller JS et al (2016) Lymphodepleting chemotherapy with donor lymphocyte infusion post-allogeneic HCT for hematological malignancies is associated with severe, but therapy-responsive aGvHD. Bone Marrow Transplant 51:1107–1112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Miller JS, Weisdorf DJ, Burns LJ et al (2007) Lymphodepletion followed by donor lymphocyte infusion (DLI) causes significantly more acute graft-versus-host disease than DLI alone. Blood 110:2761–2763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang Y, Liu QF, Xu LP et al (2015) Haploidentical vs identical-sibling transplant for AML in remission: a multicenter, prospective study. Blood 125:3956–3962

    Article  CAS  PubMed  Google Scholar 

  20. Wang Y, Liu DH, Liu KY et al (2013) Long-term follow-up of haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for the treatment of leukemia: nine years of experience at a single center. Cancer 119:978–985

    Article  PubMed  Google Scholar 

  21. Huang XJ, Liu DH, Liu KY et al (2006) Haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant 38:291–297

    Article  PubMed  Google Scholar 

  22. Sorror ML, Maris MB, Storb R et al (2005) Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 106:2912–2919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Huang XJ, Liu DH, Liu KY et al (2009) Treatment of acute leukemia with unmanipulated HLA-mismatched/haploidentical blood and bone marrow transplantation. Biol Blood Marrow Transplant 15:257–265

    Article  CAS  PubMed  Google Scholar 

  24. Zhao XS, Liu YR, Zhu HH et al (2012) Monitoring MRD with flow cytometry: an effective method to predict relapse for ALL patients after allogeneic hematopoietic stem cell transplantation. Ann Hematol 91:183–192

    Article  CAS  PubMed  Google Scholar 

  25. Zhao XS, Jin S, Zhu HH et al (2012) Wilms’ tumor gene 1 expression: an independent acute leukemia prognostic indicator following allogeneic hematopoietic SCT. Bone Marrow Transplant 47:499–507

    Article  CAS  PubMed  Google Scholar 

  26. Zhao XS, Yan CH, Liu DH et al (2013) Combined use of WT1 and flow cytometry monitoring can promote sensitivity of predicting relapse after allogeneic HSCT without affecting specificity. Ann Hematol 92:1111–1119

    Article  CAS  PubMed  Google Scholar 

  27. Huang XJ, Liu DH, Liu KY et al (2007) Donor lymphocyte infusion for the treatment of leukemia relapse after HLA-mismatched/haploidentical T-cell-replete hematopoietic stem cell transplantation. Haematologica 92:414–417

    Article  PubMed  Google Scholar 

  28. Yan C, Xu L, Liu D et al (2014) Immunosuppression for 6-8 weeks after modified donor lymphocyte infusion reduced acute graft-versus-host disease without influencing graft-versus-leukemia effect in haploidentical transplant. Chin Med J 127:3602–3609

    PubMed  Google Scholar 

  29. Dignan FL, Clark A, Amrolia P et al (2012) Diagnosis and management of acute graft-versus-host disease. Br J Haematol 158:30–45

    Article  CAS  PubMed  Google Scholar 

  30. Dignan FL, Amrolia P, Clark A et al (2012) Diagnosis and management of chronic graft-versus-host disease. Br J Haematol 158:46–61

    Article  CAS  PubMed  Google Scholar 

  31. Armand P, Gibson CJ, Cutler C et al (2012) A disease risk index for patients undergoing allogeneic stem cell transplantation. Blood 120:905–913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Przepiorka D, Weisdorf D, Martin P et al (1995) 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant 15:825–828

    CAS  PubMed  Google Scholar 

  33. Filipovich AH, Weisdorf D, Pavletic S et al (2005) National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11:945–956

    Article  PubMed  Google Scholar 

  34. Holtan SG, DeFor TE, Lazaryan A et al (2015) Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation. Blood 125:1333–1338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gooley TA, Leisenring W, Crowley J, Storer BE (1999) Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 18:695–706

    Article  CAS  PubMed  Google Scholar 

  36. Yan CH, Xu LP, Liu DH et al (2015) Low-dose methotrexate may preserve a stronger antileukemic effect than that of cyclosporine after modified donor lymphocyte infusion in unmanipulated haploidentical HSCT. Clin Transpl 29:594–605

    Article  CAS  Google Scholar 

  37. Mo XD, Zhang XH, Xu LP et al (2016) Salvage chemotherapy followed by granulocyte colony-stimulating factor-primed donor leukocyte infusion with graft-vs.-host disease control for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation: prognostic factors and clinical outcomes. Eur J Haematol 96:297–308

    Article  CAS  PubMed  Google Scholar 

  38. de Lima M, Bonamino M, Vasconcelos Z et al (2001) Prophylactic donor lymphocyte infusions after moderately ablative chemotherapy and stem cell transplantation for hematological malignancies: high remission rate among poor prognosis patients at the expense of graft-versus-host disease. Bone Marrow Transplant 27:73–78

    Article  PubMed  Google Scholar 

  39. Schmid C, Labopin M, Nagler A et al (2007) Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol 25:4938–4945

    Article  CAS  PubMed  Google Scholar 

  40. Huang XJ, Wang Y, Liu DH et al (2009) Administration of short-term immunosuppressive agents after DLI reduces the incidence of DLI-associated acute GVHD without influencing the GVL effect. Bone Marrow Transplant 44:309–316

    Article  CAS  PubMed  Google Scholar 

  41. Ringdén O, Horowitz MM, Sondel P et al (1993) Methotrexate, cyclosporine, or both to prevent graft-versus-host disease after HLA-identical sibling bone marrow transplants for early leukemia? Blood 81:1094–1101

    PubMed  Google Scholar 

  42. Bäckman L, Ringdén O, Tollemar J, Lönnqvist B (1988) An increased risk of relapse in cyclosporin-treated compared with methotrexate-treated patients: long-term follow-up of a randomized trial. Bone Marrow Transplant 3:463–471

    PubMed  Google Scholar 

  43. Mo XD, Xu LP, Liu DH et al (2013) The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) is an outcome predictor for partially matched related donor transplantation. Am J Hematol 88:497–502

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Editage for providing editorial assistance. This work was supported by the National Natural Science Foundation of China (No. 81400145), the Beijing Talents fund (No. 2015000021223ZK39), the Key Program of the National Natural Science Foundation of China (No. 81530046), and the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (No. 81621001).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xiao-Jun Huang.

Ethics declarations

Informed consent was obtained from all patients or the patients’ guardians, and the study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of Peking University People’s Hospital.

Conflicts of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mo, XD., Zhang, XH., Xu, LP. et al. Comparison of outcomes after donor lymphocyte infusion with or without prior chemotherapy for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation. Ann Hematol 96, 829–838 (2017). https://doi.org/10.1007/s00277-017-2960-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-017-2960-7

Keywords

Navigation