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Conditioning Regimens

Achieving stringent CR is essential before reduced-intensity conditioning allogeneic hematopoietic cell transplantation in AML

Bone Marrow Transplantation volume 48, pages 1415–1420 (2013)Cite this article

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A Corrigendum to this article was published on 06 November 2013

Abstract

Reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (allo-HCT) can cure patients with AML in CR. However, relapse after RIC allo-HCT may indicate heterogeneity in the stringency of CR. Strict definition of CR requires no evidence of leukemia by both morphologic and flow cytometric criteria. We re-evaluated 85 AML patients receiving RIC allo-HCT in CR to test if a strict definition of CR had direct implications for the outcome. These patients had leukemia immunophenotype documented at diagnosis and analyzed at allo-HCT. Eight (9.4%) had persistent leukemia by flow cytometric criteria at allo-HCT. The patients with immunophenotypic persistent leukemia had a significantly increased relapse (hazard ratio (HR): 3.7; 95% confidence interval (CI): 1.3–10.3, P=0.01) and decreased survival (HR: 2.9; 95% CI: 1.3–6.4, P<0.01) versus 77 patients in CR by both morphology and flow cytometry. However, the pre-allo-HCT bone marrow (BM) blast count (that is, 0–4%) was not significantly associated with risks of relapse or survival. These data indicate the presence of leukemic cells, but not the BM blast count affects survival. A strict morphologic and clinical lab flow cytometric definition of CR predicts outcomes after RIC allo-HCT, and therefore is critical to achieve at transplantation.

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References

  1. Gupta V, Tallman MS, Weisdorf DJ . Allogeneic hematopoietic cell transplantation for adults with acute myeloid leukemia: myths, controversies, and unknowns. Blood 2011; 117: 2307–2318.

    Article  CAS  PubMed  Google Scholar 

  2. Oran B, Wagner JE, DeFor TE, Weisdorf DJ, Brunstein CG . Effect of conditioning regimen intensity on acute myeloid leukemia outcomes after umbilical cord blood transplantation. Biol Blood Marrow Transplant 2011; 17: 1327–1334.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ringden O, Labopin M, Gluckman E, Reiffers J, Vernant JP, Jouet JP et al. Graft-versus-leukemia effect in allogeneic marrow transplant recipients with acute leukemia is maintained using cyclosporin A combined with methotrexate as prophylaxis. Bone Marrow Transplant 1996; 18: 921–929.

    CAS  PubMed  Google Scholar 

  4. Burnett AK, Wheatley K, Goldstone AH, Stevens RF, Hann IM, Rees JHK et al. The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: Results of the UK MRC AML 10 trial. Br J Haematol 2002; 118: 385–400.

    Article  PubMed  Google Scholar 

  5. Cornelissen JJ, van Putten WLJ, Verdonck LF, Theobald M, Jacky E, Daenen SMG et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? Blood 2007; 109: 3658–3666.

    Article  CAS  PubMed  Google Scholar 

  6. Sandmaier BM, Maloney DG, McSweeney P, Niederwieser D, Shizuru J, Chauncey J et al. Nonmyeloablative conditioning for stem cell allografts with low-dose TBI: an update of toxicity and outcome. Exp Hematol 2000; 28: 60–60.

    Article  Google Scholar 

  7. Majhail NS, Brunstein CG, Shanley R, Sandhu K, McClune B, Oran B et al. Reduced-intensity hematopoietic cell transplantation in older patients with AML/MDS: umbilical cord blood is a feasible option for patients without HLA-matched sibling donors. Bone Marrow Transplant 2012; 47: 494–498.

    Article  CAS  PubMed  Google Scholar 

  8. Mohty M, de Lavallade H, El-Cheikh J, Ladaique P, Faucher C, Furst S et al. Reduced intensity conditioning allogeneic stem cell transplantation for patients with acute myeloid leukemia: long term results of a 'donor' versus 'no donor' comparison. Leukemia 2009; 23: 194–196.

    Article  CAS  PubMed  Google Scholar 

  9. Baron F, Maris MB, Sandmaier BM, Storer BE, Sorror M, Diaconescu R et al. Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol 2005; 23: 1993–2003.

    Article  PubMed  Google Scholar 

  10. Goldman FD, Rumelhart SL, DeAlacron P, Holida MD, Lee NF, Miller J et al. Poor outcome in children with refractory/relapsed leukemia undergoing bone marrow transplantation with mismatched family member donors. Bone Marrow Transplant 2000; 25: 943–948.

    Article  CAS  PubMed  Google Scholar 

  11. Duval M, Klein JP, He W, Cahn JY, Cairo M, Camitta BM et al. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol 2010; 28: 3730–3738.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Michallet M, Thomas X, Vernant JP, Kuentz M, Socie G, Esperou-Bourdeau H et al. Long-term outcome after allogeneic hematopoietic stem cell transplantation for advanced stage acute myeloblastic leukemia: a retrospective study of 379 patients reported to the Societe Francaise de Greffe de Moelle (SFGM). Bone Marrow Transplant 2000; 26: 1157–1163.

    Article  CAS  PubMed  Google Scholar 

  13. Nemecek ER, Gooley TA, Woolfrey AE, Carpenter PA, Matthews DC, Sanders JE . Outcome of allogeneic bone marrow transplantation for children with advanced acute myeloid leukemia. Bone Marrow Transplant 2004; 34: 799–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kebriaei P, Kline J, Stock W, Kasza K, Le Beau MM, Larson RA et al. Impact of disease burden at time of allogeneic stem cell transplantation in adults with acute myeloid leukemia and myelodysplastic syndromes. Bone Marrow Transplant 2005; 35: 965–970.

    Article  CAS  PubMed  Google Scholar 

  15. Blum W, Bolwell BJ, Phillips G, Farag SS, Lin TS, Avalos BR et al. High disease burden is associated with poor outcomes for patients with acute myeloid leukemia not in remission who undergo unrelated donor cell transplantation. Biol Blood Marrow Tr 2006; 12: 61–67.

    Article  Google Scholar 

  16. Bishop MR, Alyea EP 3rd, Cairo MS, Falkenburg JH, June CH, Kroger N et al. National Cancer Institute's First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: summary and recommendations from the organizing committee. Biol Blood Marrow Transplant 2011; 17: 443–454.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Flynn CM, Hirsch B, Defor T, Barker JN, Miller JS, Wagner JE et al. Reduced intensity compared with high dose conditioning for allotransplantation in acute myeloid leukemia and myelodysplastic syndrome: a comparative clinical analysis. Am J Hematol 2007; 82: 867–872.

    Article  PubMed  Google Scholar 

  18. Aoudjhane M, Labopin M, Gorin NC, Shimoni A, Ruutu T, Kolb HJ et al. Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT). Leukemia 2005; 19: 2304–2312.

    Article  CAS  PubMed  Google Scholar 

  19. Alyea EP, Kim HT, Ho V, Cutler C, DeAngelo DJ, Stone R et al. Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant 2006; 12: 1047–1055.

    Article  PubMed  Google Scholar 

  20. Alyea EP, Kim HT, Ho V, Cutler C, Gribben J, DeAngelo DJ et al. Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age. Blood 2005; 105: 1810–1814.

    Article  CAS  PubMed  Google Scholar 

  21. Shimoni A, Hardan I, Shem-Tov N, Yeshurun M, Yerushalmi R, Avigdor A et al. Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity. Leukemia 2006; 20: 322–328.

    Article  CAS  PubMed  Google Scholar 

  22. Martino R, Iacobelli S, Brand R, Jansen T, van Biezen A, Finke J et al. Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood 2006; 108: 836–846.

    Article  CAS  PubMed  Google Scholar 

  23. Ringden O, Labopin M, Ehninger G, Niederwieser D, Olsson R, Basara N et al. Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. J Clin Oncol 2009; 27: 4570–4577.

    Article  PubMed  Google Scholar 

  24. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH et al. Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 2003; 21: 4642–4649.

    Article  PubMed  Google Scholar 

  25. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005; 106: 2912–2919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000; 96: 4075–4083.

    CAS  PubMed  Google Scholar 

  27. Brunstein CG, Barker JN, Weisdorf DJ, DeFor TE, Miller JS, Blazar BR et al. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood 2007; 110: 3064–3070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, Miller JS, Wagner JE . Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning. Blood 2003; 102: 1915–1919.

    Article  CAS  PubMed  Google Scholar 

  29. Dunning K, Safo AO . The ultimate Wright-Giemsa stain: 60 years in the making. Biotechnol Histochem 2011; 86: 69–75.

    Article  CAS  Google Scholar 

  30. Kaplan EL, Meier P . Nonparametric-Estimation from Incomplete Observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  31. Lin DY . Non-parametric inference for cumulative incidence functions in competing risks studies. Stat Med 1997; 16: 901–910.

    Article  CAS  PubMed  Google Scholar 

  32. Cox DR . Regression models and life tables. J R Stat Soc Bull 1972; 34: 187–220.

    Google Scholar 

  33. Fine JP, Gray RJ . A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496–509.

    Article  Google Scholar 

  34. Paietta E . Minimal residual disease in acute myeloid leukemia: coming of age. Hematology Am Soc Hematol Educ Program 2012; 2012: 35–42.

    PubMed  Google Scholar 

  35. Oran B, Popat U, Rondon G, Ravandi F, Garcia-Manero G, Abruzzo L et al. Significance of persistent cytogenetic abnormalities on myeloablative allogeneic stem cell transplantation in first complete remission. Biol Blood Marrow Transplant 2013; 19: 214–220.

    Article  PubMed  Google Scholar 

  36. Engel H, Drach J, Keyhani A, Jiang S, Van NT, Kimmel M et al. Quantitation of minimal residual disease in acute myelogenous leukemia and myelodysplastic syndromes in complete remission by molecular cytogenetics of progenitor cells. Leukemia 1999; 13: 568–577.

    Article  CAS  PubMed  Google Scholar 

  37. Kwon M, Martinez-Laperche C, Infante M, Carretero F, Balsalobre P, Serrano D et al. Evaluation of minimal residual disease by real-time quantitative PCR of Wilms' tumor 1 expression in patients with acute myelogenous leukemia after allogeneic stem cell transplantation: correlation with flow cytometry and chimerism. Biol Blood Marrow Transplant 2012; 18: 1235–1242.

    Article  CAS  PubMed  Google Scholar 

  38. Perea G, Lasa A, Aventin A, Domingo A, Villamor N, de Llano MPQ et al. Prognostic value of minimal residual disease (MRD) in acute myeloid leukemia (AML) with favorable cytogenetics [t(8;21) and inv(16)]. Leukemia 2006; 20: 87–94.

    Article  CAS  PubMed  Google Scholar 

  39. Jourdan E, Boissel N, Chevret S, Delabesse E, Renneville A, Cornillet P et al. Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia. Blood 2013; 121: 2213–2223.

    Article  CAS  PubMed  Google Scholar 

  40. Walter RB, Gooley TA, Wood BL, Milano F, Fang M, Sorror ML et al. Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemia. J Clin Oncol 2011; 29: 1190–1197.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Loken MR, Alonzo TA, Pardo L, Gerbing RB, Raimondi SC, Hirsch BA et al. Residual disease detected by multidimensional flow cytometry signifies high relapse risk in patients with de novo acute myeloid leukemia: a report from Children's Oncology Group. Blood 2012; 120: 1581–1588.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Kamble RT, Hjortsvang E, Selby GB . Leukemia burden and outcome of allogeneic transplant in acute myelogenous leukemia. Biol Blood Marrow Transplant 2006; 12: 691–692.

    Article  PubMed  Google Scholar 

  43. Gyurkocza B, Storb R, Storer BE, Chauncey TR, Lange T, Shizuru JA et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol 2010; 28: 2859–2867.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Oran B, Giralt S, Saliba R, Hosing C, Popat U, Khouri I et al. Allogeneic hematopoietic stem cell transplantation for the treatment of high-risk acute myelogenous leukemia and myelodysplastic syndrome using reduced-intensity conditioning with fludarabine and melphalan. Biol Blood Marrow Transplant 2007; 13: 454–462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sayer HG, Kroger M, Beyer J, Kiehl M, Klein SA, Schaefer-Eckart K et al. Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia: disease status by marrow blasts is the strongest prognostic factor. Bone Marrow Transplant 2003; 31: 1089–1095.

    Article  CAS  PubMed  Google Scholar 

  46. Elmaagacli AH, Steckel NK, Koldehoff M, Hegerfeldt Y, Trenschel R, Ditschkowski M et al. Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients. Blood 2011; 118: 1402–1412.

    Article  CAS  PubMed  Google Scholar 

  47. Foley B, Cooley S, Verneris MR, Pitt M, Curtsinger J, Luo XH et al. Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C(+) natural killer cells with potent function. Blood 2012; 119: 2665–2674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ossenkoppele G, Schuurhuis GJ . MRD in AML: time for redefinition of CR? Blood 2013; 121: 2166–2168.

    Article  CAS  PubMed  Google Scholar 

  49. Inaba H, Coustan-Smith E, Cao X, Pounds SB, Shurtleff SA, Wang KY et al. Comparative analysis of different approaches to measure treatment response in acute myeloid leukemia. J Clin Oncol 2012; 30: 3625–3632.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Burke MJ, Burns L, Linden MA, Lindgren B, Verneris MR, Weisdorf D et al. How do we define complete remission for acute myeloid leukemia in the current era? Results of an international survey. Am J Hematol, (e-pub ahead of print 4 June 2013; doi:10.1002/ajh.23497).

  51. Leung W, Pui CH, Coustan-Smith E, Yang J, Pei D, Gan K et al. Detectable minimal residual disease before hematopoietic cell transplantation is prognostic but does not preclude cure for children with very-high-risk leukemia. Blood 2012; 120: 468–472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wayne AS, Radich JP . Pretransplant MRD: the light is yellow, not red. Blood 2012; 120: 244–246.

    Article  CAS  PubMed  Google Scholar 

  53. Kim DY, Lee JH, Park YH, Lee JH, Kim SD, Choi Y et al. Feasibility of hypomethylating agents followed by allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome. Bone Marrow Transplant 2012; 47: 374–379.

    Article  CAS  PubMed  Google Scholar 

  54. Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH, Fautsch SK et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 2005; 105: 3051–3057.

    Article  CAS  PubMed  Google Scholar 

  55. Warlick ED, Tomblyn M, Cao Q, Defor T, Blazar BR, Macmillan M et al. Reduced-intensity conditioning followed by related allografts in hematologic malignancies: long-term outcomes most successful in indolent and aggressive non-Hodgkin lymphomas. Biol Blood Marrow Transplant 2011; 17: 1025–1032.

    Article  PubMed  Google Scholar 

  56. Tallman MS, Rowlings PA, Milone G, Zhang MJ, Perez WS, Weisdorf D et al. Effect of postremission chemotherapy before human leukocyte antigen-identical sibling transplantation for acute myelogenous leukemia in first complete remission. Blood 2000; 96: 1254–1258.

    CAS  PubMed  Google Scholar 

  57. Buckley SA, Appelbaum FR, Walter RB . Prognostic and therapeutic implications of minimal residual disease at the time of transplantation in acute leukemia. Bone Marrow Transplant 2013; 48: 630–641.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Hematology, Department of Medicine, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA

    C Ustun, B Oran, E Warlick, J S Miller & D Weisdorf

  2. Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN, USA

    C Ustun, A C Wiseman, T E DeFor, M Burke, E Warlick, J S Miller & D Weisdorf

  3. Medical School, University of Minnesota, Minneapolis, MN, USA

    S Yohe & M A Linden

  4. Division of Hematopathology, Department of Laboratory Medicine and Pathology, University of Minnesota, MN, USA

    M Burke

  5. Division of Hematology-Oncology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA

    M Burke

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  1. C Ustun
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Ustun, C., Wiseman, A., DeFor, T. et al. Achieving stringent CR is essential before reduced-intensity conditioning allogeneic hematopoietic cell transplantation in AML. Bone Marrow Transplant 48, 1415–1420 (2013). https://doi.org/10.1038/bmt.2013.124

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