Annals of Hematology

, Volume 98, Issue 3, pp 753–762 | Cite as

Comparable outcome after haploidentical and HLA-matched allogeneic stem cell transplantation for high-risk acute myeloid leukemia following sequential conditioning—a matched pair analysis

  • Maximilian DoppelhammerEmail author
  • Alessia Fraccaroli
  • Dusan Prevalsek
  • Veit Bücklein
  • Sarah Häbe
  • Christoph Schulz
  • Max Hubmann
  • Andreas Hausmann
  • Rainer Claus
  • Andreas Rank
  • Christoph Schmid
  • Johanna Tischer
Original Article


In acute myeloid leukemia (AML), primary refractory or relapsed disease, secondary AML, and leukemia with unfavorable genetics are considered high-risk AML (hrAML), with allogeneic stem cell transplantation (SCT) representing the standard treatment. Sequential conditioning has been successfully used for SCT in hrAML in HLA-matched transplants, and found its way into HLA-haploidentical SCT (haplo-SCT) later on. Hence, sequential conditioning had become standard for all patients with hrAML in our two centers, regardless of donor type. Thereby, HLA-matched family or unrelated transplants were first/second choice, post-transplant cyclophosphamide (PTCY)-based haplo-SCT was chosen in patients missing matched donors or requiring urgent transplantation. To compare the outcome after HLA-matched and haplo-SCT for hrAML following sequential conditioning, we performed a retrospective, matched-pair comparison, using disease stage, genetic subgroups and age as matching criteria. Thirty-four well-matched pairs were identified. At SCT, patients (median age 54 years) were untreated (9%), had remission (13%), or active disease (78%). Three-year overall and leukemia-free survival (OS/LFS) of the entire cohort was 56 ± 7%/49 ± 7%, without significant differences between donor types (OS after HLA-matched/haplo-SCT 62 ± 10%/52 ± 9% (p = 0.21), LFS 53 ± 10%/46 ± 9% (p = 0.26)). Similarly, the cumulative incidence of relapse, non-relapse-mortality and chronic GvHD, as well as GvHD-free, relapse-free survival (GRFS), and chronic GvHD-free, relapse-free survival (cGRFS), were comparable. However, a higher incidence of acute GvHD ≥ II° was observed after HLA-matched SCT (15 ± 1% versus 50 ± 2%, p = 0.001). In conclusion, sequential conditioning SCT achieved remarkable results in hrAML, independently from donor type. PTCY-based haplo-SCT produced results that were comparable to HLA-matched SCT and can be used as an alternative option.


AML High-risk AML Haploidentical stem cell transplantation Sequential conditioning FLAMSA-RIC 



The authors wish to acknowledge the dedicated work of our nurses in both transplant units, as well as an excellent data management by M. Rothmayer, A. Bader, and D. Engels.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing financial interests.

Supplementary material

277_2019_3593_MOESM1_ESM.xlsx (12 kb)
ESM 1 (XLSX 12 kb)


  1. 1.
    Estey EH (2012) How to manage high-risk acute myeloid leukemia. Leukemia 26(5):861–869. CrossRefGoogle Scholar
  2. 2.
    Schiller GJ (2013) High-risk acute myelogenous leukemia: treatment today ... and tomorrow. Hematology Am Soc Hematol Educ Program 2013:201–208. CrossRefGoogle Scholar
  3. 3.
    Abdul Wahid SF, Ismail NA, Mohd-Idris MR, Jamaluddin FW, Tumian N, Sze-Wei EY, Muhammad N, Nai ML (2014) Comparison of reduced-intensity and myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and acute lymphoblastic leukemia: a meta-analysis. Stem Cells Dev 23(21):2535–2552. CrossRefGoogle Scholar
  4. 4.
    Schmid C, Schleuning M, Schwerdtfeger R, Hertenstein B, Mischak-Weissinger E, Bunjes D, Harsdorf SV, Scheid C, Holtick U, Greinix H, Keil F, Schneider B, Sandherr M, Bug G, Tischer J, Ledderose G, Hallek M, Hiddemann W, Kolb HJ (2006) Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood 108(3):1092–1099. CrossRefGoogle Scholar
  5. 5.
    Holtick U, Shimabukuro-Vornhagen A, Chakupurakal G, Theurich S, Leitzke S, Burst A, Hallek M, von Bergwelt-Baildon M, Scheid C, Chemnitz JM (2016) FLAMSA reduced-intensity conditioning is equally effective in AML patients with primary induction failure as well as in first or second complete remission. Eur J Haematol 96(5):475–482. CrossRefGoogle Scholar
  6. 6.
    Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, Gooley TA, Piantadosi S, Kaup M, Ambinder RF, Huff CA, Matsui W, Bolanos-Meade J, Borrello I, Powell JD, Harrington E, Warnock S, Flowers M, Brodsky RA, Sandmaier BM, Storb RF, Jones RJ, Fuchs EJ (2008) HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 14(6):641–650. CrossRefGoogle Scholar
  7. 7.
    Passweg JR, Baldomero H, Bader P, Bonini C, Duarte RF, Dufour C, Gennery A, Kroger N, Kuball J, Lanza F, Montoto S, Nagler A, Snowden JA, Styczynski J, Mohty M (2017) Use of haploidentical stem cell transplantation continues to increase: the 2015 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant 52(6):811–817. CrossRefGoogle Scholar
  8. 8.
    Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK, Morris LE, Bashey A (2012) Haploidentical transplantation using T cell replete peripheral blood stem cells and myeloablative conditioning in patients with high-risk hematologic malignancies who lack conventional donors is well tolerated and produces excellent relapse-free survival: results of a prospective phase II trial. Biol Blood Marrow Transplant 18(12):1859–1866. CrossRefGoogle Scholar
  9. 9.
    Raiola AM, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F, Bregante S, Van Lint MT, Geroldi S, Luchetti S, Ballerini F, Miglino M, Varaldo R, Bacigalupo A (2013) Unmanipulated haploidentical bone marrow transplantation and posttransplantation cyclophosphamide for hematologic malignancies after myeloablative conditioning. Biol Blood Marrow Transplant 19(1):117–122. CrossRefGoogle Scholar
  10. 10.
    Tischer J, Stemmler HJ, Engel N, Hubmann M, Fritsch S, Prevalsek D, Schulz C, Zoellner AK, Bucklein V, Hill W, Ledderose G, Hausmann A (2013) Feasibility of clofarabine cytoreduction followed by haploidentical hematopoietic stem cell transplantation in patients with relapsed or refractory advanced acute leukemia. Ann Hematol 92(10):1379–1388. CrossRefGoogle Scholar
  11. 11.
    Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Lowenberg B, Bloomfield CD (2010) Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 115(3):453–474. CrossRefGoogle Scholar
  12. 12.
    Schmid C, Schleuning M, Ledderose G, Tischer J, Kolb HJ (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(24):5675–5687. CrossRefGoogle Scholar
  13. 13.
    Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME, Maziarz RT, Antin JH, Soiffer RJ, Weisdorf DJ, Rizzo JD, Horowitz MM, Saber W (2014) Validation and refinement of the disease risk index for allogeneic stem cell transplantation. Blood 123(23):3664–3671. CrossRefGoogle Scholar
  14. 14.
    Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, Storer B (2005) Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 106(8):2912–2919. CrossRefGoogle Scholar
  15. 15.
    Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Lowenberg B, Bloomfield CD (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129(4):424–447. CrossRefGoogle Scholar
  16. 16.
    Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED (1995) 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant 15(6):825–828Google Scholar
  17. 17.
    Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME (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(12):945–956. CrossRefGoogle Scholar
  18. 18.
    De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, Pappas PG, Maertens J, Lortholary O, Kauffman CA, Denning DW, Patterson TF, Maschmeyer G, Bille J, Dismukes WE, Herbrecht R, Hope WW, Kibbler CC, Kullberg BJ, Marr KA, Munoz P, Odds FC, Perfect JR, Restrepo A, Ruhnke M, Segal BH, Sobel JD, Sorrell TC, Viscoli C, Wingard JR, Zaoutis T, Bennett JE (2008) Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46(12):1813–1821. CrossRefGoogle Scholar
  19. 19.
    McCurdy SR, Kasamon YL, Kanakry CG, Bolanos-Meade J, Tsai HL, Showel MM, Kanakry JA, Symons HJ, Gojo I, Smith BD, Bettinotti MP, Matsui WH, Dezern AE, Huff CA, Borrello I, Pratz KW, Gladstone DE, Swinnen LJ, Brodsky RA, Levis MJ, Ambinder RF, Fuchs EJ, Rosner GL, Jones RJ, Luznik L (2017) Comparable composite endpoints after HLA-matched and HLA-haploidentical transplantation with post-transplantation cyclophosphamide. Haematologica 102(2):391–400. CrossRefGoogle Scholar
  20. 20.
    Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53(282):457–481. CrossRefGoogle Scholar
  21. 21.
    Gray RJ (1988) A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16(3):1141–1154CrossRefGoogle Scholar
  22. 22.
    Schmid C, Schleuning M, Tischer J, Holler E, Haude KH, Braess J, Haferlach C, Baurmann H, Oruzio D, Hahn J, Spiekermann K, Schlimok G, Schwerdtfeger R, Buechner T, Hiddemann W, Kolb HJ (2012) Early allo-SCT for AML with a complex aberrant karyotype—results from a prospective pilot study. Bone Marrow Transplant 47(1):46–53. CrossRefGoogle Scholar
  23. 23.
    Malard F, Labopin M, Stuhler G, Bittenbring J, Ganser A, Tischer J, Michallet M, Kroger N, Schmid C, Huynh A, Hallek M, Savani BN, Mohty M, Nagler A (2017) Sequential intensified conditioning regimen allogeneic hematopoietic stem cell transplantation in adult patients with intermediate- or high-risk acute myeloid leukemia in complete remission: a study from the acute leukemia working Party of the European Group for blood and marrow transplantation. Biol Blood Marrow Transplant 23(2):278–284. CrossRefGoogle Scholar
  24. 24.
    Ringden O, Labopin M, Schmid C, Sadeghi B, Polge E, Tischer J, Ganser A, Michallet M, Kanz L, Schwerdtfeger R, Nagler A, Mohty M (2017) Sequential chemotherapy followed by reduced-intensity conditioning and allogeneic haematopoietic stem cell transplantation in adult patients with relapse or refractory acute myeloid leukaemia: a survey from the Acute Leukaemia Working Party of EBMT. Br J Haematol 176(3):431–439. CrossRefGoogle Scholar
  25. 25.
    Tischer J, Engel N, Fritsch S, Prevalsek D, Hubmann M, Schulz C, Zoellner AK, Bucklein V, Lippl S, Reibke R, Rieger CT, Ledderose G, Stemmler HJ, Hiddemann W, Schmid C, Hausmann A (2014) Second haematopoietic SCT using HLA-haploidentical donors in patients with relapse of acute leukaemia after a first allogeneic transplantation. Bone Marrow Transplant 49(7):895–901. CrossRefGoogle Scholar
  26. 26.
    Raiola AM, Dominietto A, di Grazia C, Lamparelli T, Gualandi F, Ibatici A, Bregante S, Van Lint MT, Varaldo R, Ghiso A, Gobbi M, Carella AM, Signori A, Galaverna F, Bacigalupo A (2014) Unmanipulated haploidentical transplants compared with other alternative donors and matched sibling grafts. Biol Blood Marrow Transplant 20 (10):1573–1579.
  27. 27.
    Ciurea SO, Zhang MJ, Bacigalupo AA, Bashey A, Appelbaum FR, Aljitawi OS, Armand P, Antin JH, Chen J, Devine SM, Fowler DH, Luznik L, Nakamura R, O'Donnell PV, Perales MA, Pingali SR, Porter DL, Riches MR, Ringden OT, Rocha V, Vij R, Weisdorf DJ, Champlin RE, Horowitz MM, Fuchs EJ, Eapen M (2015) Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood 126(8):1033–1040. CrossRefGoogle Scholar
  28. 28.
    Ruggeri A, Labopin M, Bacigalupo A, Gulbas Z, Koc Y, Blaise D, Bruno B, Irrera G, Tischer J, Diez-Martin JL, Castagna L, Ciceri F, Mohty M, Nagler A (2018) Bone marrow versus mobilized peripheral blood stem cells in haploidentical transplants using posttransplantation cyclophosphamide. Cancer 124:1428–1437. CrossRefGoogle Scholar
  29. 29.
    Bashey A, Zhang MJ, McCurdy SR, St Martin A, Argall T, Anasetti C, Ciurea SO, Fasan O, Gaballa S, Hamadani M, Munshi P, Al Malki MM, Nakamura R, O'Donnell PV, Perales MA, Raj K, Romee R, Rowley S, Rocha V, Salit RB, Solh M, Soiffer RJ, Fuchs EJ, Eapen M (2017) Mobilized peripheral blood stem cells versus unstimulated bone marrow as a graft source for T-cell-replete haploidentical donor transplantation using post-transplant cyclophosphamide. J Clin Oncol 35(26):3002–3009. CrossRefGoogle Scholar
  30. 30.
    Di Stasi A, Milton DR, Poon LM, Hamdi A, Rondon G, Chen J, Pingali SR, Konopleva M, Kongtim P, Alousi A, Qazilbash MH, Ahmed S, Bashir Q, Al-atrash G, Oran B, Hosing CM, Kebriaei P, Popat U, Shpall EJ, Lee DA, de Lima M, Rezvani K, Khouri IF, Champlin RE, Ciurea SO (2014) Similar transplantation outcomes for acute myeloid leukemia and myelodysplastic syndrome patients with haploidentical versus 10/10 human leukocyte antigen-matched unrelated and related donors. Biol Blood Marrow Transplant 20 (12):1975–1981.
  31. 31.
    Piemontese S, Ciceri F, Labopin M, Arcese W, Kyrcz-Krzemien S, Santarone S, Huang H, Beelen D, Gorin NC, Craddock C, Gulbas Z, Bacigalupo A, Mohty M, Nagler A (2017) A comparison between allogeneic stem cell transplantation from unmanipulated haploidentical and unrelated donors in acute leukemia. J Hematol Oncol 10(1):24. CrossRefGoogle Scholar
  32. 32.
    Versluis J, Labopin M, Ruggeri A, Socie G, Wu D, Volin L, Blaise D, Milpied N, Craddock C, Yakoub-Agha I, Maertens J, Ljungman P, Huynh A, Michallet M, Deconinck E, Chevallier P, Passweg J, Ciceri F, Mohty M, Cornelissen JJ, Nagler A (2017) Alternative donors for allogeneic hematopoietic stem cell transplantation in poor-risk AML in CR1. Blood advances 1(7):477–485. CrossRefGoogle Scholar
  33. 33.
    How J, Slade M, Vu K, DiPersio JF, Westervelt P, Uy GL, Abboud CN, Vij R, Schroeder MA, Fehniger TA, Romee R (2017) T cell-replete peripheral blood haploidentical hematopoietic cell transplantation with post-transplantation cyclophosphamide results in outcomes similar to transplantation from traditionally matched donors in active disease acute myeloid leukemia. Biol Blood Marrow Transplant 23(4):648–653. CrossRefGoogle Scholar
  34. 34.
    Ciceri F, Labopin M, Aversa F, Rowe JM, Bunjes D, Lewalle P, Nagler A, Di Bartolomeo P, Lacerda JF, Lupo Stanghellini MT, Polge E, Frassoni F, Martelli MF, Rocha V (2008) A survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation. Blood 112(9):3574–3581. CrossRefGoogle Scholar
  35. 35.
    Dulery R, Menard AL, Chantepie S, Cheikh JE, Francois S, Delage J, Giannotti F, Ruggeri A, Brissot E, Battipaglia G, Malard F, Belhocine R, Sestili S, Vekhoff A, Delhommeau F, Reman O, Legrand O, Labopin M, Rubio MT, Mohty M (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. CrossRefGoogle Scholar
  36. 36.
    McCurdy SR, Kanakry JA, Showel MM, Tsai HL, Bolanos-Meade J, Rosner GL, Kanakry CG, Perica K, Symons HJ, Brodsky RA, Gladstone DE, Huff CA, Pratz KW, Prince GT, Dezern AE, Gojo I, Matsui WH, Borrello I, McDevitt MA, Swinnen LJ, Smith BD, Levis MJ, Ambinder RF, Luznik L, Jones RJ, Fuchs EJ, Kasamon YL (2015) Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide. Blood 125(19):3024–3031. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Maximilian Doppelhammer
    • 1
    Email author
  • Alessia Fraccaroli
    • 2
  • Dusan Prevalsek
    • 2
  • Veit Bücklein
    • 2
  • Sarah Häbe
    • 2
  • Christoph Schulz
    • 2
  • Max Hubmann
    • 2
    • 3
  • Andreas Hausmann
    • 2
    • 4
  • Rainer Claus
    • 1
  • Andreas Rank
    • 1
  • Christoph Schmid
    • 1
  • Johanna Tischer
    • 2
  1. 1.Department of Medicine II, Stem Cell Transplantation Unit, Klinikum AugsburgLudwig-Maximilians University MunichMunichGermany
  2. 2.Department of Medicine III, Stem Cell Transplantation Unit, University HospitalLudwig-Maximilians University MunichMunichGermany
  3. 3.Praxis für Hämatologie und OnkologieHerrschingGermany
  4. 4.Department of Hematology and OncologyKlinikum SchwabingMunichGermany

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