CTLA4Ig-primed donor lymphocyte infusions following haploidentical transplantation improve outcome with a distinct pattern of early immune reconstitution as compared to conventional donor lymphocyte infusions in advanced hematological malignancies

Abstract

CTLA4Ig has a unique property to spare or even potentiate natural killer (NK) cell-mediated cytotoxicity, whilst inhibiting T cell activation. We explored the efficacy of prophylactic DLI following CTLA4Ig (CTLA4Ig-DLI group, n = 75), compared to conventional DLI (DLI group, n = 50), in patients with advanced hematological malignancies receiving PTCy-based haploidentical transplantation. Acute and chronic GVHD in the CTLA4Ig-DLI group were 9.6% and 15.3% compared to 18.8% [p = 0.09] and 36.5% [p = 0.01] in the DLI group. Both non-relapse mortality (4% vs 14.4%) and disease progression (DP) (15.7% vs 31.1%) were lower in CTLA4Ig-DLI group (p = 0.04). GVHD and progression-free survival was significantly improved in the CTLA4Ig-DLI group (p = 0.001). The recovery of CD56dimNK cells, NKG2A-KIR + NK subsets and Tregs was significantly better in the CTLA4Ig-DLI group at all time points and memory T cells at day +90. Immune recovery in relation to DP showed distinct patterns, with T cell subsets in the DLI group and NKG2A-KIR+NK cells in CTLA4Ig-DLI group having favorable impact. CTLA4Ig-DLI was thus associated with an improved outcome, possibly on account of the distinct pattern of immune recovery shown with this novel approach.

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: Transplantation protocols.
Fig. 2: Comparison of transplant outcomes.
Fig. 3: GVHD and progression-free survival.
Fig. 4: Comparison of immune reconstitution.

References

  1. 1.

    Spyridonidis A, Labopin M, Savani BN, Niittyvuopio R, Blaise D, Craddock C, et al. Redefining and measuring transplant conditioning intensity in current era: a study in acute myeloid leukemia patients. Bone Marrow Transplant. 2020;55:1114–25.

    CAS  Article  Google Scholar 

  2. 2.

    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. 2019;105:47–58.

    Article  Google Scholar 

  3. 3.

    Zeiser R, Vago L. Mechanisms of immune escape after allogeneic hematopoietic cell transplantation. Blood. 2019;133:1290–7.

    CAS  Article  Google Scholar 

  4. 4.

    Toffalori C, Cavattoni I, Deola S, Mastaglio S, Giglio F, Mazzi B, et al. Genomic loss of patient-specific HLA in acute myeloid leukemia relapse after well-matched unrelated donor HSCT. Blood. 2012;119:4813–5.

    CAS  Article  Google Scholar 

  5. 5.

    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 Transplant. 2016;22:1867–73.

    CAS  Article  Google Scholar 

  6. 6.

    Jaiswal SR, Aiyer HM, Rawat G, Gera A, Chakrabarti S. CTLA4Ig-based reduced intensity conditioning and donor lymphocyte infusions for haploidentical transplantation in refractory aggressive B-cell lymphoma relapsing after an autograft: early results from a pilot study. Exp Hematol. 2019;77:26–35 e1.

    CAS  Article  Google Scholar 

  7. 7.

    Jaiswal SR, Bhakuni P, Joy A, Kaushal S, Chakrabarti A, Chakrabarti S. CTLA4Ig primed donor lymphocyte infusion: a novel approach to immunotherapy after haploidentical transplantation for advanced leukemia. Biol Blood Marrow Transplant. 2019;25:673–82.

    CAS  Article  Google Scholar 

  8. 8.

    Jaiswal SR, Zaman S, Nedunchezhian M, Chakrabarti A, Bhakuni P, Ahmed M, et al. CD56-enriched donor cell infusion after post-transplantation cyclophosphamide for haploidentical transplantation of advanced myeloid malignancies is associated with prompt reconstitution of mature natural killer cells and regulatory T cells with reduced incidence of acute graft versus host disease: A pilot study. Cytotherapy. 2017;19:531–42.

    CAS  Article  Google Scholar 

  9. 9.

    Jaiswal SR, Chakrabarti A, Chatterjee S, Bhargava S, Ray K, O’Donnell P, et al. Haploidentical peripheral blood stem cell transplantation with post-transplantation cyclophosphamide in children with advanced acute leukemia with fludarabine-, busulfan-, and melphalan-based conditioning. Biol Blood Marrow Transplant. 2016;22:499–504.

    CAS  Article  Google Scholar 

  10. 10.

    Jaiswal SR, Singhal P, Thatai A, Bhagwati G, Aiyer HM, Chakrabarti A, et al. Impact of extended infusional mesna prophylaxis on the incidence of BK viruria and hemorrhagic cystitis following post-transplantation cyclophosphamide and CTLA4Ig-based haploidentical transplantation. Ann Hematol. 2020;99:839–45.

    CAS  Article  Google Scholar 

  11. 11.

    Jaiswal SR, Bhakuni P, Zaman S, Bansal S, Bharadwaj P, Bhargava S, et al. T cell costimulation blockade promotes transplantation tolerance in combination with sirolimus and post-transplantation cyclophosphamide for haploidentical transplantation in children with severe aplastic anemia. Transpl Immunol. 2017;43-44:54–9.

    CAS  Article  Google Scholar 

  12. 12.

    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 Transplant. 2012;47:1099–104.

    CAS  Article  Google Scholar 

  13. 13.

    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 Transplant. 2017;23:1311–9.

    Article  Google Scholar 

  14. 14.

    Huang XJ, Wang Y, Liu DH, Xu LP, Chen H, Chen YH, et al. Modified donor lymphocyte infusion (DLI) for the prophylaxis of leukemia relapse after hematopoietic stem cell transplantation in patients with advanced leukemia–feasibility and safety study. J Clin Immunol. 2008;28:390–7.

    CAS  Article  Google Scholar 

  15. 15.

    Jaiswal SR, Chakrabarti A, Chatterjee S, Ray K, Chakrabarti S. Haploidentical transplantation in children with unmanipulated peripheral blood stem cell graft: the need to look beyond post-transplantation cyclophosphamide in younger children. Pediatr Transplant. 2016;20:675–82.

    CAS  Article  Google Scholar 

  16. 16.

    Russo A, Oliveira G, Berglund S, Greco R, Gambacorta V, Cieri N, et al. NK cell recovery after haploidentical HSCT with posttransplant cyclophosphamide: dynamics and clinical implications. Blood. 2018;131:247–62.

    CAS  Article  Google Scholar 

  17. 17.

    Chen Y, Fukuda T, Thakar MS, Kornblit BT, Storer BE, Santos EB, et al. Immunomodulatory effects induced by cytotoxic T lymphocyte antigen 4 immunoglobulin with donor peripheral blood mononuclear cell infusion in canine major histocompatibility complex-haplo-identical non-myeloablative hematopoietic cell transplantation. Cytotherapy. 2011;13:1269–80.

    CAS  Article  Google Scholar 

  18. 18.

    Kean LS, Hamby K, Koehn B, Lee E, Coley S, Stempora L, et al. NK cells mediate costimulation blockade-resistant rejection of allogeneic stem cells during nonmyeloablative transplantation. Am J Transplant. 2006;6:292–304.

    CAS  Article  Google Scholar 

  19. 19.

    Peng Y, Luo G, Zhou J, Wang X, Hu J, Cui Y, et al. CD86 is an activation receptor for NK cell cytotoxicity against tumor cells. PLoS One. 2013;8:e83913.

    Article  Google Scholar 

  20. 20.

    Ohata K, Espinoza JL, Lu X, Kondo Y, Nakao S. Mycophenolic acid inhibits natural killer cell proliferation and cytotoxic function: a possible disadvantage of including mycophenolate mofetil in the graft-versus-host disease prophylaxis regimen. Biol Blood Marrow Transplant. 2011;17:205–13.

    CAS  Article  Google Scholar 

  21. 21.

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

    CAS  Article  Google Scholar 

  22. 22.

    McCurdy SR, Kanakry JA, Showel MM, Tsai HL, Bolanos-Meade J, Rosner GL, et al. Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide. Blood. 2015;125:3024–31.

    CAS  Article  Google Scholar 

  23. 23.

    Comoli P, Locatelli F, Moretta A, Montagna D, Calcaterra V, Cometa A, et al. Human alloantigen-specific anergic cells induced by a combination of CTLA4-Ig and CsA maintain anti-leukemia and anti-viral cytotoxic responses. Bone Marrow Transplant. 2001;27:1263–73.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank all the patients and family members who participated in this study. We also thank each and every member of our department for their help in patient care and execution of the study.

Author information

Affiliations

Authors

Contributions

SRJ and SC designed and performed the study. SRJ and PB performed the experiments. HMA, MS, NS and PB collected the data. SRJ, RRJ, GB and SC analyzed the data; SRJ, AC and SC wrote the manuscript. All the co-authors reviewed and approved the manuscript.

Corresponding author

Correspondence to Sarita Rani Jaiswal.

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.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Jaiswal, S.R., Bhakuni, P., Bhagawati, G. et al. CTLA4Ig-primed donor lymphocyte infusions following haploidentical transplantation improve outcome with a distinct pattern of early immune reconstitution as compared to conventional donor lymphocyte infusions in advanced hematological malignancies. Bone Marrow Transplant (2020). https://doi.org/10.1038/s41409-020-01002-1

Download citation

Search