Skip to main content
SpringerLink
Log in

Impact of prophylactic/preemptive donor lymphocyte infusion and intensified conditioning for relapsed/refractory leukemia: a real-world study

  • Research Paper
  • Published:
Science China Life Sciences Aims and scope Submit manuscript

Abstract

Prophylactic/preemptive donor lymphocyte infusion (p/pDLI) and intensified conditioning have shown promising results in experimental studies of refractory/relapsed acute leukemia (RRAL), but real-world data remain scarce. We conducted a multicenter, population-based analysis of 932 consecutive patients. The three-year leukemia-free survival (LFS) rates were 56% for patients receiving both p/pDLI and intensified myeloablative conditioning (MAC) (intenseMAC) and 30% for those who received neither therapy per landmark analysis. Multivariable analyses were run separately for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), and p/pDLI treatment was linked to significantly higher LFS than non-DLI for both AML and ALL patients without increasing the nonrelapse mortality. IntenseMAC was associated with significantly lower relapse and higher LFS than nonintensified MAC despite higher nonrelapse mortality rates in ALL, while there was no impact of intenseMAC observed in AML. p/pDLI achieved superior outcomes in both matched-sibling donor (MSD) and haploidentical donor transplantation, while intenseMAC only influenced MSD outcomes. Data suggest that RRAL patients receiving “total therapy” by way of p/pDLI and intensified conditioning treatment have an improved chance for LFS, with p/pDLI being safer with a more extensive impact relative to intenseMAC. Patients with RRAL can tolerate both interventions and achieve a reasonable outcome.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Bornhäuser M., Kienast J., Trenschel R., Burchert A., Hegenbart U., Stadler M., Baurmann H., Schäfer-Eckart K., Holler E., Kröger N., et al. (2012). Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol 13, 1035–1044.

    Article  Google Scholar 

  • Dickinson A.M., Norden J., Li S., Hromadnikova I., Schmid C., Schmetzer H., and Jochem-Kolb H. (2017). Graft-versus-leukemia effect following hematopoietic stem cell transplantation for leukemia. Front Immunol 8, 496.

    Article  Google Scholar 

  • Duléry R., Ménard A.L., Chantepie S., El-Cheikh J., François S., Delage J., Giannotti F., Ruggeri A., Brissot E., Battipaglia G., et al. (2018). Sequential conditioning with thiotepa in T cell-replete hematopoietic stem cell transplantation for the treatment of refractory hematologic malignancies: comparison with matched related, haplo-mismatched, and unrelated donors. Biol Blood Marrow Transplant 24, 1013–1021.

    Article  Google Scholar 

  • Duval M., Klein J.P., He W., Cahn J.Y., Cairo M., Camitta B.M., Kamble R., Copelan E., de Lima M., Gupta V., et al. (2010). Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol 28, 3730–3738.

    Article  Google Scholar 

  • Jaiswal S.R., Zaman S., Chakrabarti A., Sen S., Mukherjee S., Bhargava S., Ray K., O’Donnell P.V., and Chakrabarti S. (2016). 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 Transplant 22, 1867–1873.

    Article  CAS  Google Scholar 

  • Karpanen T., and Olweus J. (2017). The potential of donor T-cell repertoires in neoantigen-targeted cancer immunotherapy. Front Immunol 8, 1718.

    Article  Google Scholar 

  • Liu Q.F., Fan Z.P., Zhang Y., Jiang Z.J., Wang C.Y., Xu D., Sun J., Xiao Y., and Tan H. (2009). Sequential intensified conditioning and tapering of prophylactic immunosuppressants for graft-versus-host disease in allogeneic hematopoietic stem cell transplantation for refractory leukemia. Biol Blood Marrow Transplant 15, 1376–1385.

    Article  CAS  Google Scholar 

  • Liu Y., Huang X., Fei Q., Xu L., Zhang X., Liu K., Chen Y., Chen H., and Wang Y. (2019). Comparison analysis between haplo identical stem cell transplantation and matched sibling donor stem cell transplantation for high-risk acute myeloid leukemia in first complete remission. Sci China Life Sci 62, 691–697.

    Article  Google Scholar 

  • Martino R., de Wreede L., Fiocco M., van Biezen A., von dem Borne P. A., Hamladji R.M., Volin L., Bornhäuser M., Robin M., Rocha V., et al. (2013). Comparison of conditioning regimens of various intensities for allogeneic hematopoietic SCT using HLA-identical sibling donors in AML and MDS with <10% BM blasts: a report from EBMT. Bone Marrow Transplant 48, 761–770.

    Article  CAS  Google Scholar 

  • McClune B.L., Weisdorf D.J., Pedersen T.L., Tunes da Silva G., Tallman M.S., Sierra J., Dipersio J., Keating A., Gale R.P., George B., et al. (2010). Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol 28, 1878–1887.

    Article  Google Scholar 

  • Mo X.D., Zhang X.H., Xu L.P., Wang Y., Yan C.H., Chen H., Chen Y. H., Han W., Wang F.R., Wang J.Z., et al. (2017). 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.

    Article  Google Scholar 

  • Mohty M., Malard F., Blaise D., Milpied N., Socié, G., Huynh A., Reman O., Yakoub-Agha I., Furst S., Guillaume T., et al. (2017). Sequential regimen of clofarabine, cytosine arabinoside and reduced-intensity conditioned transplantation for primary refractory acute myeloid leukemia. Haematologica 102, 184–191.

    Article  CAS  Google Scholar 

  • Moorman A.V., Harrison C.J., Buck G.A.N., Richards S.M., Secker-Walker L.M., Martineau M., Vance G.H., Cherry A.M., Higgins R. R., Fielding A.K., et al. (2007). Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood 109, 3189–3197.

    Article  CAS  Google Scholar 

  • Przepiorka D., Weisdorf D., Martin P., Klingemann H.G., Beatty P., Hows J., and Thomas E.D. (1995). 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 15, 825–828.

    CAS  PubMed  Google Scholar 

  • Rubio M.T., Savani B.N., Labopin M., Piemontese S., Polge E., Ciceri F., Bacigalupo A., Arcese W., Koc Y., Beelen D., et al. (2016). Impact of conditioning intensity in T-replete haplo-identical stem cell transplantation for acute leukemia: a report from the acute leukemia working party of the EBMT. J Hematol Oncol 9, 25.

    Article  Google Scholar 

  • Ruggeri A., Battipaglia G., Labopin M., Ehninger G., Beelen D., Tischer J., Ganser A., Schwerdtfeger R., Glass B., Finke J., et al. (2016). Unrelated donor versus matched sibling donor in adults with acute myeloid leukemia in first relapse: an ALWP-EBMT study. J Hematol Oncol 9, 89.

    Article  Google Scholar 

  • Schmid C., Schleuning M., Ledderose G., Tischer J., and Kolb H.J. (2005). Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 23, 5675–5687.

    Article  Google Scholar 

  • Shulman H.M., Sullivan K.M., Weiden P.L., McDonald G.B., Striker G. E., Sale G.E., Hackman R., Tsoi M.S., Storb R., and Donnall Thomas E. (1980). Chronic graft-versus-host syndrome in man. Am J Med 69, 204–217.

    Article  CAS  Google Scholar 

  • Wang Y., Chang Y.J., Xu L.P., Liu K.Y., Liu D.H., Zhang X.H., Chen H., Han W., Chen Y.H., Wang F.R., et al. (2014). Who is the best donor for a related HLA haplotype-mismatched transplant? Blood 124, 843–850.

    Article  CAS  Google Scholar 

  • Wang Y., Chen H., Chen J., Han M., Hu J.D., Jiong Hu J.D., Huang H., Lai Y., Liu D., Liu Q., et al. (2018a). The consensus on the monitoring, treatment, and prevention of leukemia relapse after allogeneic hematopoietic stem cell transplantation in China. Cancer Lett 438, 63–75.

    Article  CAS  Google Scholar 

  • Wang Y., Liu D.H., Xu L.P., Liu K.Y., Chen H., Chen Y.H., Han W., Shi H.X., and Huang X.J. (2011). Superior graft-versus-leukemia effect associated with transplantation of haploidentical compared with HLA-identical sibling donor grafts for high-risk acute leukemia: an historic comparison. Biol Blood Marrow Transplant 17, 821–830.

    Article  Google Scholar 

  • Wang Y., Liu D.H., Xu L.P., Liu K.Y., Chen H., Zhang X.H., Chen Y. H., Han W., Wang F.R., Wang J.Z., et al. (2012). 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 Transplant 47, 1099–1104.

    Article  CAS  Google Scholar 

  • Wang Y., Liu Q.F., Xu L.P., Liu K.Y., Zhang X.H., Ma X., Fan Z.P., Wu D.P., and Huang X.J. (2015). Haploidentical vs identical-sibling transplant for AML in remission: a multicenter, prospective study. Blood 125, 3956–3962.

    Article  CAS  Google Scholar 

  • Wang Y., Liu Q.F., Xu L.P., Liu K.Y., Zhang X.H., Ma X., Wu M.Q., Wu D.P., and Huang X.J. (2016). Haploidentical versus matched-sibling transplant in adults with philadelphia-negative high-risk acute lymphoblastic leukemia: a biologically phase III randomized study. Clin Cancer Res 22, 3467–3476.

    Article  CAS  Google Scholar 

  • Wang Y., Wu D.P., Liu Q.F., Xu L.P., Liu K.Y., Zhang X.H., Xu Y., Huang F., and Huang X.J. (2018b). Donor and recipient age, gender and ABO incompatibility regardless of donor source: validated criteria for donor selection for haematopoietic transplants. Leukemia 32, 492–498.

    Article  CAS  Google Scholar 

  • Wang Y., Xu L., Yan C., and Huang X. (2019). Modification of donor lymphocyte infusion: how to improve the outcome? Sci China Life Sci 62, 1253–1256.

    Article  Google Scholar 

  • Weisdorf D.J., Millard H.R., Horowitz M.M., Hyare P.S., Champlin R., Ho V., Mielcarek M., Rezvani A., Stockerl-Goldstein K., Khoury H.J., et al. (2017). Allogeneic transplantation for advanced acute myeloid leukemia: The value of complete remission. Cancer 123, 2025–2034.

    Article  CAS  Google Scholar 

  • Wu Q., Zhang R., Wang H., You Y., Zhong Z., Hong M., Fang J., Li W., Shi W., Lu X., et al. (2015). Comparison of outcomes of idarubicin intensified TBI–CY and traditional TBI–CY conditioning regimen for high-risk acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation: A single center experience. Leuk Res pii: S0145–2126(15)30369–6.

    Google Scholar 

  • Xu L., Chen H., Chen J., Han M., Huang H., Lai Y., Liu D., Liu Q., Liu T., Jiang M., et al. (2018). The consensus on indications, conditioning regimen, and donor selection of allogeneic hematopoietic cell transplantation for hematological diseases in China— recommendations from the Chinese Society of Hematology. J Hematol Oncol 11, 33.

    Article  Google Scholar 

  • Xuan L., Fan Z., Zhang Y., Zhou H., Huang F., Dai M., Nie D., Lin D., Xu N., Guo X., et al. (2016). Sequential intensified conditioning followed by prophylactic DLI could reduce relapse of refractory acute leukemia after allo-HSCT. Oncotarget 7, 32579–32591.

    Article  Google Scholar 

  • Yan C.H., Liu Q.F., Wu D.P., Zhang X., Xu L.P., Zhang X.H., Wang Y., Huang H., Bai H., Huang F., et al. (2017). 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 Transplant 23, 1311–1319.

    Article  Google Scholar 

  • Zhang R., Shi W., Wang H.F., You Y., Zhong Z.D., Li W.M., Zhang C., Lu X., Wang Y.D., Zheng P., et al. (2017). Idarubicin-intensified haploidentical HSCT with GvHD prophylaxis of ATG and basiliximab provides comparable results to sibling donors in high-risk acute leukemia. Bone Marrow Transplant 52, 1253–1260.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was partly supported by grants from the National Key Research and Development Program of China (2017YFA0104500) from the Ministry of Science and Technology, National Natural Science Foundation of China (81770189, 81621001, and 81530046), CAMS Innovation Fund for Medical Sciences (CIFMS) (2019-I2M-5-034), Collaborative Innovation Center of Hematology China, the Science and Technology Project of Guangdong Province of China (2016B030230003), Peking University Clinical Scientist Program (BMU2019LCKXJ003), the Fundamental Research Funds for the Central Universities, and the Project of Health Collaborative Innovation of Guangzhou City (201704020214). We thank the principal investigators and the skilled teams at each of the participating sites.

Author information

Author notes

  1. Contributed equally to this work

Authors and Affiliations

  1. Department of Hematology, Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China

    Yu Wang, Lan-Ping Xu, Chen-Hua Yan & Xiao-Jun Huang

  2. Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Qi-Fa Liu

  3. Department of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China

    De-Pei Wu

  4. Department of Hematology, Aero Center Space Hospital, Beijing, 100049, China

    Jing-Bo Wang

  5. Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China

    Xi Zhang

  6. Department of Hematology, Air Force General Hospital, PLA, Beijing, 100142, China

    Heng-Xiang Wang

  7. Department of Hematology, the Affiliated Hospital of North China University Science and Technology, Tangshan, 063210, China

    Feng Gao

  8. Department of Hematology, Guangzhou First People’s Hospital, Guangzhou, 510180, China

    Shun-Qing Wang

  9. Department of Hematology, Anhui Provincial Hospital, Hefei, 230001, China

    Zi-Min Sun

  10. Department of Hematology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China

    Jian Ouyang

  11. Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China

    Kai-Lin Xu

  12. Department of Hematology, the First Affiliated Hospital of Jilin University, Changchun, 130021, China

    Su-Jun Gao

  13. Peking-Tsinghua Center for Life Sciences, Beijing, 100871, China

    Xiao-Jun Huang

  14. Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, 2019RU029, Beijing, 100730, China

    Lan-Ping Xu, Chen-Hua Yan & Xiao-Jun Huang

  15. Collaborative Innovation Center of Hematology, Beijing, 100044, China

    Yu Wang, De-Pei Wu & Xiao-Jun Huang

Authors
  1. Yu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qi-Fa Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. De-Pei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing-Bo Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Heng-Xiang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Feng Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shun-Qing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zi-Min Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jian Ouyang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kai-Lin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Su-Jun Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Lan-Ping Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Chen-Hua Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Xiao-Jun Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiao-Jun Huang.

Additional information

Compliance and ethics

The author(s) declare that they have no conflict of interest. We state that our studies conform with the Helsinki Declaration of 1975 (as revised in 2008) concerning Human and Animal Rights and that they followed the policy concerning Informed Consent as shown on Springer.com.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Y., Liu, QF., Wu, DP. et al. Impact of prophylactic/preemptive donor lymphocyte infusion and intensified conditioning for relapsed/refractory leukemia: a real-world study. Sci. China Life Sci. 63, 1552–1564 (2020). https://doi.org/10.1007/s11427-019-1610-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11427-019-1610-2

Keywords

Search

Navigation