How to reduce the risk of primary engraftment failure after haploidentical hematopoietic stem cell transplantation in patients with acute myeloid leukemia?

   Background. Haploidentical hematopoietic stem cell transplantation (haplo‑HSCT) represents an important alternative for patients with acute myeloid leukemia (AML) who lack an HLA‑matched donor. However, the high incidence of primary graft failure remains a significant challenge. Optimizing transplantation strategies, including the selection of the graft source and modification of conditioning regimens, may improve haplo‑HSCT outcomes.

   Aim. To evaluate the results of haplo‑HSCT in AML patients in first remission, focusing on engraftment rates and the factors influencing them.

   Materials and methods. Seventy‑three AML patients in first remission who underwent haplo‑HSCT between 2015 and 2024 were included in the study. Engraftment was defined as achieving an absolute neutrophil count of ≥ 0.5 × 10⁹ / L and a leukocyte count of ≥ 1 × 10⁹ / L for three consecutive days and was assessed using cumulative incidence functions with death as a competing event.

   Results. The engraftment rate was 80.8 % (95 % confidence interval (CI) 69.5–88.3) with a median time of 20 (15–31) days. A higher probability of engraftment was associated with the use of peripheral blood stem cells as the graft source (hazard ratio (HR) 2.62; 95 % CI 1.5–4.58; p < 0.001), myeloablative conditioning (HR 2.29; 95 % CI 1.17–4.45; p = 0.015), a higher Cd34+ cell count in the graft (HR 1.17; 95 % CI 1.05–1.31; p = 0.004), pre‑transplant biological therapy (HR 2.28; 95 % CI 1.33–3.91; p = 0.003), and the inclusion of bendamustine in the conditioning regimen (HR 2.32; 95 % CI 1.33–4.03; p = 0.003). Moreover, the use of peripheral blood stem cells, myeloablative conditioning, and bendamustine significantly reduced the time to engraftment (p = 0.016; p = 0.017; and p = 0.033, respectively). An increased level of Cd34+ cells in the graft correlated with faster engraftment (R = –0.34; p = 0.009). The engraftment rate after a second transplantation was 55.6 % (95 % CI 16.9–82.3).

   Conclusion. Haplo‑HSCT remains an important therapeutic option for AML patients in first remission, although its efficacy is limited by the risk of primary graft failure. The use of peripheral blood stem cells, myeloablative conditioning regimens, and modified protocols incorporating bendamustine enhances the probability of engraftment. Of additional interest is the observed positive effect of preceding venetoclax‑based biological therapy. despite the high risk of transplant‑related mortality, a second transplantation appears to be an optimal strategy in cases of primary graft failure.

1. Passweg J.R., Baldomero H., Ciceri F. et al. Hematopoietic cell transplantation and cellular therapies in Europe 2022. CAR­T activity continues to grow; transplant activity has slowed: a report from the EBMT. Bone Marrow Transplant 2024;59(6):803–12. DOI: 10.1038/s41409­024­02248­9

2. Cusatis R., Litovich C., Feng Z. et al. Current trends and outcomes in cellular therapy activity in the United States, including prospective Patient Reported Outcomes data collection within the CIBMTR registry. Transplant Cell Ther 2024;30(9):917.e1–7. DOI: 10.1016/j.jtct.2024.06.021

3. Kindwall­Keller T.L., Ballen K.K. Alternative donor graft sources for adults with hematologic malignancies: a donor for all patients in 2017! Oncologist 2017;22(9):1125–34. DOI: 10.1634/theoncologist.2017­0009

4. Gragert L., Eapen M., Williams E. et al. HLA match likelihoods for hematopoietic stem­cell grafts in the U.S. registry. N Engl J Med 2014;371(4):339–48. DOI: 10.1056/NEJMsa1311707

5. Dehn J., Buck K., Maiers M. et al. 8/8 and 10/10 high­resolution match rate for the be the match unrelated donor registry. Biol Blood Marrow Transplant 2015;21(1):137–41. DOI: 10.1016/j.bbmt.2014.10.002

6. Parovichnikova E.N., Kuzmina L.A., Vasilyeva V.A. et al. The time factor and the allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia. Gematologiya i transfuziologiya = Russian Journal of Hematology and Transfusiology 2024;69(3):276–84. (In Russ.). DOI: 10.35754/0234­5730­2024­69­3­276­284

7. Anasetti C., Beatty P.G., Storb R. et al. Effect of HLA incompatibility on graft­versus­host disease, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma. Hum Immunol 1990;29(2):79–91. DOI: 10.1016/0198­8859(90)90071­v

8. Dey B.R., Spitzer T.R. Current status of haploidentical stem cell transplantation. Br J Haematol 2006;135(4):423–37. DOI: 10.1111/j.1365­2141.2006.06300.x

9. Beynarovich A.V., Babenko E.V., Moiseev I.S. et al. Haploidentical stem cell transplantation in adults for the treatment of hematologic diseases: results of a single center (CIC725). Cell Ther Transplant 2019;8(1):26–35. DOI: 10.18620/ctt­1866­8836­2019­8­1­26­35

10. Luznik L., O’Donnell P.V., Symons H.J. et al. HLA-­haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high­dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008;14(6): 641–50. DOI: 10.1016/j.bbmt.2008.03.005

11. Phelan R., Chen M., Bupp C. et al. Updated trends in hematopoietic cell transplantation in the United States with an additional focus on adolescent and young adult transplantation activity and outcomes. Transplant Cell Ther 2022;28(7):409.e1–10. DOI: 10.1016/j.jtct.2022.04.012

12. Zhogolev D.K., Bondarenko S.N., Smirnova A.G. et al. Role of haploidentical donor in allogeneic hematopoietic stem cell transplantation with cyclophosphamide­based GvHD prophylaxis regimens in first remission of acute myeloid leukemia. Cell Ther Transplant 2024;13(3):20–30. DOI: 10.18620/ctt­1866­8836­2024­13­3­20­30

13. Rudakova T.A., Yakimenko E.S., Volkov N.P. et al. Salvage second allogeneic stem cell transplantation for primary and secondary graft failure in adult patients. Cell Ther Transplant 2023;12(2):15–22. DOI: 10.18620/ctt­1866­8836­2023­12­2­15­22

14. Ruggeri A., Labopin M., Bacigalupo A. et al. Bone marrow versus mobilized peripheral blood stem cells in haploidentical transplants using posttransplantation cyclophosphamide. Cancer 2018;124(7):1428–37. DOI: 10.1002/cncr.31228

15. Jiménez­Antolinez V., Colunga­Pedraza J., Gómez­-De León A. et al. Lesson learned in pediatric haploidentical transplantation in a low­resource environment: delivering melphalan IV and using low dose radiation reduce graft failure. Hematology 2024;29(1):2335417. DOI: 10.1080/16078454.2024.2335417

16. Kharya G., Jaiswal S.R., Bhat S. et al. Impact of conditioning regimen and graft­versus­host disease prophylaxis on the outcome of haploidentical peripheral blood stem cell transplantation for high­risk severe aplastic anemia in children and young adults: a report from the Pediatric Severe Aplastic Anemia Consortium of India. Transplant Cell Ther 2023;29(3):199.e1–10. DOI: 10.1016/j.jtct.2022.12.010

17. Alessandrino E.P., Bernasconi P., Colombo A.A. et al. Thiotepa and fludarabine (TT­FLUDA) as conditioning regimen in poor candidates for conventional allogeneic hemopoietic stem cell transplant. Ann Hematol 2001;80(9):521–4. DOI: 10.1007/s002770100344

18. Moiseev I.S., Cherkashina A.N., Rudakova T.A. et al. Low incidence of primary graft failure with bendamustine, fludarabine, and busulfan conditioning prior to haploidentical allogeneic hematopoietic cell transplantation. Hematol Oncol Stem Cell Ther 2024;17(4):219–26. DOI: 10.4103/hemoncstem.HEMONCSTEM­D­24­00026

19. Ciurea S.O., Thall P.F., Milton D.R. et al. Complement­binding donor­specific anti­-HLA antibodies and risk of primary graft failure in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2015;21(8):1392–8. DOI: 10.1016/j.bbmt.2015.05.001

20. Ciurea S.O., Cao K., Fernandez-­Vina M. et al. The European Society for Blood and Marrow Transplantation (EBMT) consensus guidelines for the detection and treatment of donor­specific anti­-HLA antibodies (DSA) in haploidentical hematopoietic cell transplantation. Bone Marrow Transplant 2018;53(5):521–34. DOI: 10.1038/s41409­017­0062­8

21. Ciurea S.O., Al Malki M.M., Kongtim P. et al. Treatment of all sensitized patients receiving allogeneic transplantation. Blood Adv 2021;5(20):4031–43. DOI: 10.1182/bloodadvances.2021004862

22. Locatelli F., Lucarelli B., Merli P. Current and future approaches to treat graft failure after allogeneic hematopoietic stem cell transplantation. Expert Opin Pharmacother 2014;15(1):23–36. DOI: 10.1517/14656566.2014.852537

23. Vlachonikola E., Sofou E., Gerousi M. et al. Longitudinal profiling of the T cell compartment in patients with chronic lymphocytic leukemia treated with venetoclax. Blood 2022;140(Suppl 1):9891–2. DOI: 10.1182/blood­2022­162173

24. Cao X.Y., Chen J.Q., Wang H. et al. Addition of venetoclax to myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in high­risk AML. Ann Med 2023;55(1):388–400. DOI: 10.1080/07853890.2022.2164610