Advertisement

Annals of Hematology

, Volume 93, Issue 7, pp 1097–1110 | Cite as

Relapse assessment following allogeneic SCT in patients with MDS and AML

  • Maximilian Christopeit
  • Nicolaus Kröger
  • Torsten Haferlach
  • Ulrike Bacher
Review Article

Abstract

Options to pre-emptively treat impending relapse of myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) after allogeneic haematopoietic stem cell transplantation (allo-SCT) continuously increase. In recent years, the spectrum of diagnostic methods and parameters to perform post-transplant monitoring in patients with AML and MDS has grown. Cytomorphology, histomorphology, and chimaerism analysis are the mainstay in any panel of post-transplant monitoring. This may be individually combined with multiparameter flow cytometry (MFC) for the detection of residual cells with a leukaemia phenotype and quantitative real-time polymerase chain reaction (RQ-PCR) to assess gene expression, e.g., of WT1 or the residual mutation load (e.g., in case of an NPM1 mutation). Data evaluating the aforementioned methods alone or in combination are discussed in this review with particular emphasis on data pointing towards their suitability to steer pre-emptive post-transplant interventions such as immunotherapy, chemotherapy or therapy with demethylating agents.

Keywords

Minimal residual disease (MRD) Post-transplant period Relapse risk Acute myeloid leukaemia (AML) Myelodysplastic syndrome (MDS) 

Notes

Conflict of interest

TH declares part ownership of the MLL Munich Leukemia Laboratory. MC, NK, and UB declare that they have no disclosures to make.

References

  1. 1.
    Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, Habdank M, Spath D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Döhner H, German–Austrian Acute Myeloid Leukemia Study G (2008) Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 358(18):1909–1918PubMedGoogle Scholar
  2. 2.
    Koreth J, Schlenk R, Kopecky KJ, Honda S, Sierra J, Djulbegovic BJ, Wadleigh M, DeAngelo DJ, Stone RM, Sakamaki H, Appelbaum FR, Dohner H, Antin JH, Soiffer RJ, Cutler C (2009) Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 301(22):2349–2361PubMedCentralPubMedGoogle Scholar
  3. 3.
    Kröger N, Bacher U, Bader P, Bottcher S, Borowitz MJ, Dreger P, Khouri I, Macapinlac HA, Olavarria E, Radich J, Stock W, Vose JM, Weisdorf D, Willasch A, Giralt S, Bishop MR, Wayne AS (2010) NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: report from the Committee on Disease-Specific Methods and Strategies for Monitoring Relapse following Allogeneic Stem Cell Transplantation: Part I. Methods, acute leukemias, and myelodysplastic syndromes. Biol Blood Marrow Transplant 16(9):1187–1211PubMedGoogle Scholar
  4. 4.
    Cornelissen JJ, Gratwohl A, Schlenk RF, Sierra J, Bornhäuser M, Juliusson G, Racil Z, Rowe JM, Russell N, Mohty M, Löwenberg B, Socie G, Niederwieser D, Ossenkoppele GJ (2012) The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach. Nat Rev Clinical Oncol 9(10):579–590Google Scholar
  5. 5.
    Schmid C, Labopin M, Nagler A, Niederwieser D, Castagna L, Tabrizi R, Stadler M, Kuball J, Cornelissen J, Vorlicek J, Socie G, Falda M, Vindelov L, Ljungman P, Jackson G, Kröger N, Rank A, Polge E, Rocha V, Mohty M, Acute Leukaemia Working Party of the European Group for B, Marrow T (2012) Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood 119(6):1599–1606PubMedGoogle Scholar
  6. 6.
    Christopeit M, Kuss O, Finke J, Bacher U, Beelen DW, Bornhäuser M, Schwerdtfeger R, Bethge WA, Basara N, Gramatzki M, Tischer J, Kolb HJ, Uharek L, Meyer RG, Bunjes D, Scheid C, Martin H, Niederwieser D, Kröger N, Bertz H, Schrezenmeier H, Schmid C (2013) Second allograft for hematologic relapse of acute leukemia after first allogeneic stem-cell transplantation from related and unrelated donors: the role of donor change. J Clin Oncol 31(26):3259–3271PubMedGoogle Scholar
  7. 7.
    Sairafi D, Remberger M, Uhlin M, Ljungman P, Ringden O, Mattsson J (2010) Leukemia lineage-specific chimerism analysis and molecular monitoring improve outcome of donor lymphocyte infusions. Biol Blood Marrow Transplant 16(12):1728–1737PubMedGoogle Scholar
  8. 8.
    Bacher U, Zander AR, Haferlach T, Schnittger S, Fehse B, Kröger N (2008) Minimal residual disease diagnostics in myeloid malignancies in the post transplant period. Bone Marrow Transplant 42(3):145–157PubMedGoogle Scholar
  9. 9.
    Buckley SA, Appelbaum FR, Walter RB (2013) Prognostic and therapeutic implications of minimal residual disease at the time of transplantation in acute leukemia. Bone Marrow Transplant 48(5):630–641PubMedGoogle Scholar
  10. 10.
    Walter RB, Buckley SA, Pagel JM, Wood BL, Storer BE, Sandmaier BM, Fang M, Gyurkocza B, Delaney C, Radich JP, Estey EH, Appelbaum FR (2013) Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission. Blood 122(10):1813–1821PubMedGoogle Scholar
  11. 11.
    Cornelissen JJ (2013) Old wine in a new bottle: ready to drink? Blood 122(10):1689–1690PubMedGoogle Scholar
  12. 12.
    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):1092–1099PubMedGoogle Scholar
  13. 13.
    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):5675–5687PubMedGoogle Scholar
  14. 14.
    Pfeiffer T, Schleuning M, Mayer J, Haude KH, Tischer J, Buchholz S, Bunjes D, Bug G, Holler E, Meyer RG, Greinix H, Scheid C, Christopeit M, Schnittger S, Braess J, Schlimok G, Spiekermann K, Ganser A, Kolb HJ, Schmid C (2013) Influence of molecular subgroups on outcome of acute myeloid leukemia with normal karyotype in 141 patients undergoing salvage allogeneic stem cell transplantation in primary induction failure or beyond first relapse. Haematologica 98(4):518–525PubMedCentralPubMedGoogle Scholar
  15. 15.
    Hughes TP, Kaeda J, Branford S, Rudzki Z, Hochhaus A, Hensley ML, Gathmann I, Bolton AE, van Hoomissen IC, Goldman JM, Radich JP, International Randomised Study of Interferon versus STISG (2003) Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349(15):1423–1432PubMedGoogle Scholar
  16. 16.
    Löwenberg B (2003) Minimal residual disease in chronic myeloid leukemia. N Engl J Med 349(15):1399–1401PubMedGoogle Scholar
  17. 17.
    Cross NC, Feng L, Chase A, Bungey J, Hughes TP, Goldman JM (1993) Competitive polymerase chain reaction to estimate the number of BCR-ABL transcripts in chronic myeloid leukemia patients after bone marrow transplantation. Blood 82(6):1929–1936PubMedGoogle Scholar
  18. 18.
    Cross NC, Hughes TP, Feng L, O'Shea P, Bungey J, Marks DI, Ferrant A, Martiat P, Goldman JM (1993) Minimal residual disease after allogeneic bone marrow transplantation for chronic myeloid leukaemia in first chronic phase: correlations with acute graft-versus-host disease and relapse. Br J Haematol 84(1):67–74PubMedGoogle Scholar
  19. 19.
    Kaeda J, O'Shea D, Szydlo RM, Olavarria E, Dazzi F, Marin D, Saunders S, Khorashad JS, Cross NC, Goldman JM, Apperley JF (2006) Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplantation for chronic myeloid leukemia: an attempt to define patients who may not require further therapy. Blood 107(10):4171–4176PubMedCentralPubMedGoogle Scholar
  20. 20.
    Radich JP, Gehly G, Gooley T, Bryant E, Clift RA, Collins S, Edmands S, Kirk J, Lee A, Kessler P et al (1995) Polymerase chain reaction detection of the BCR-ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: results and implications in 346 patients. Blood 85(9):2632–2638PubMedGoogle Scholar
  21. 21.
    Olavarria E, Kanfer E, Szydlo R, Kaeda J, Rezvani K, Cwynarski K, Pocock C, Dazzi F, Craddock C, Apperley JF, Cross NC, Goldman JM (2001) Early detection of BCR-ABL transcripts by quantitative reverse transcriptase-polymerase chain reaction predicts outcome after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood 97(6):1560–1565PubMedGoogle Scholar
  22. 22.
    Mughal TI, Yong A, Szydlo RM, Dazzi F, Olavarria E, van Rhee F, Kaeda J, Cross NC, Craddock C, Kanfer E, Apperley J, Goldman JM (2001) Molecular studies in patients with chronic myeloid leukaemia in remission 5 years after allogeneic stem cell transplant define the risk of subsequent relapse. Br J Haematol 115(3):569–574PubMedGoogle Scholar
  23. 23.
    Lion T, Henn T, Gaiger A, Kalhs P, Gadner H (1993) Early detection of relapse after bone marrow transplantation in patients with chronic myelogenous leukaemia. Lancet 341(8840):275–276PubMedGoogle Scholar
  24. 24.
    Kröger N, Bacher U, Bader P, Bottcher S, Borowitz MJ, Dreger P, Khouri I, Olavarria E, Radich J, Stock W, Vose JM, Weisdorf D, Willasch A, Giralt S, Bishop MR, Wayne AS (2010) NCI first international workshop on the biology, prevention, and treatment of relapse after allogeneic hematopoietic stem cell transplantation: report from the committee on disease-specific methods and strategies for monitoring relapse following allogeneic stem cell transplantation: Part II. Chronic leukemias, myeloproliferative neoplasms, and lymphoid malignancies. Biol Blood Marrow Transplant 16(10):1325–1346PubMedGoogle Scholar
  25. 25.
    Bar M, Radich J (2013) Maintenance therapy with tyrosine kinase inhibitors after transplant in patients with chronic myeloid leukemia. J Natl Compr Cancer Netw 11(3):308–315Google Scholar
  26. 26.
    van Dongen JJ, Seriu T, Panzer-Grumayer ER, Biondi A, Pongers-Willemse MJ, Corral L, Stolz F, Schrappe M, Masera G, Kamps WA, Gadner H, van Wering ER, Ludwig WD, Basso G, de Bruijn MA, Cazzaniga G, Hettinger K, van der Does-van den Berg A, Hop WC, Riehm H, Bartram CR (1998) Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 352(9142):1731–1738PubMedGoogle Scholar
  27. 27.
    Brüggemann M, Raff T, Kneba M (2012) Has MRD monitoring superseded other prognostic factors in adult ALL? Blood 120(23):4470–4481PubMedGoogle Scholar
  28. 28.
    Paietta E (2012) When it comes to MRD, AML not equal ALL. Blood 120(8):1536–1537PubMedGoogle Scholar
  29. 29.
    Paietta E (2012) Minimal residual disease in acute myeloid leukemia: coming of age. Hematol Am Soc Hematol Educ Program 2012:35–42Google Scholar
  30. 30.
    Grimwade D, Tallman MS (2011) Should minimal residual disease monitoring be the standard of care for all patients with acute promyelocytic leukemia? Leuk Res 35(1):3–7PubMedGoogle Scholar
  31. 31.
    Kern W, Haferlach C, Haferlach T, Schnittger S (2008) Monitoring of minimal residual disease in acute myeloid leukemia. Cancer 112(1):4–16PubMedGoogle Scholar
  32. 32.
    Hokland P, Ommen HB (2011) Towards individualized follow-up in adult acute myeloid leukemia in remission. Blood 117(9):2577–2584PubMedGoogle Scholar
  33. 33.
    Kern W, Voskova D, Schoch C, Hiddemann W, Schnittger S, Haferlach T (2004) Determination of relapse risk based on assessment of minimal residual disease during complete remission by multiparameter flow cytometry in unselected patients with acute myeloid leukemia. Blood 104(10):3078–3085PubMedGoogle Scholar
  34. 34.
    Langebrake C, Brinkmann I, Teigler-Schlegel A, Creutzig U, Griesinger F, Puhlmann U, Reinhardt D (2005) Immunophenotypic differences between diagnosis and relapse in childhood AML: implications for MRD monitoring. Cytometry B Clin Cytom 63(1):1–9PubMedGoogle Scholar
  35. 35.
    Rettinger E, Willasch AM, Kreyenberg H, Borkhardt A, Holter W, Kremens B, Strahm B, Woessmann W, Mauz-Koerholz C, Gruhn B, Burdach S, Albert MH, Schlegel PG, Klingebiel T, Bader P (2011) Preemptive immunotherapy in childhood acute myeloid leukemia for patients showing evidence of mixed chimerism after allogeneic stem cell transplantation. Blood 118(20):5681–5688PubMedGoogle Scholar
  36. 36.
    Yan CH, Liu DH, Liu KY, Xu LP, Liu YR, Chen H, Han W, Wang Y, Qin YZ, Huang XJ (2012) Risk stratification-directed donor lymphocyte infusion could reduce relapse of standard-risk acute leukemia patients after allogeneic hematopoietic stem cell transplantation. Blood 119(14):3256–3262PubMedGoogle Scholar
  37. 37.
    van Marion AM, Thiele J, Kvasnicka HM, van den Tweel JG (2006) Morphology of the bone marrow after stem cell transplantation. Histopathology 48(4):329–342PubMedGoogle Scholar
  38. 38.
    Onuma T, Rosner F, Levy RN, Cuttner J, Moon JH, Silver RT, Blom J, Falkson G, Burningham R, Glidewell O, Holland JF (1971) Treatment of adult leukemia with l-asparaginase (NSC-109229). Cancer Chemother Rep 55(3):269–275PubMedGoogle Scholar
  39. 39.
    Christopeit M, Miersch K, Klyuchnikov E, Haferlach T, Binder M, Zabelina T, Ayuk F, Schafhausen P, Zander AR, Bokemeyer C, Kröger N, Bacher U (2012) Evaluation of BM cytomorphology after allo-SCT in patients with AML. Bone Marrow Transplant 47(12):1538–1544PubMedGoogle Scholar
  40. 40.
    Christopeit M, Ocheni S, Haferlach T, Miersch K, Zabelina T, Klyuchnikov E, Binder M, Ayuk F, Schafhausen P, Zander AR, Bokemeyer C, Kröger N, Bacher U (2013) Evaluation of BM cytomorphology after allo-SCT in patients with MDS. Bone Marrow Transplant 48(3):465–466PubMedGoogle Scholar
  41. 41.
    van Wering ER, van der Linden-Schrever BE, Szczepanski T, Willemse MJ, Baars EA, van Wijngaarde-Schmitz HM, Kamps WA, van Dongen JJ (2000) Regenerating normal B-cell precursors during and after treatment of acute lymphoblastic leukaemia: implications for monitoring of minimal residual disease. Br J Haematol 110(1):139–146PubMedGoogle Scholar
  42. 42.
    Duval M, Fenneteau O, Cave H, Gobillot C, Rohrlich P, Guidal C, Lescoeur B, Legac S, Schlegel N, Sterkers G, Vilmer E (1997) Expansion of polyclonal B-cell precursors in bone marrow from children treated for acute lymphoblastic leukemia. Hematol Cell Ther 39(3):139–147PubMedGoogle Scholar
  43. 43.
    Schuurmans Stekhoven JH, Langenhuysen CA, Bakkeren JA, Holland R, Holler I, De Vaan GA, Schretlen ED (1986) Morphology and incidence of the "posttherapeutic lymphoid cell" in the bone marrow of children with acute lymphoblastic leukemia. Am J Pathol 124(1):46–52PubMedCentralPubMedGoogle Scholar
  44. 44.
    Paolucci P, Hayward AR, Rapson NT (1979) Pre-B and B cells in children on leukaemia remission maintenance treatment. Clin Exp Immunol 37(2):259–266PubMedCentralPubMedGoogle Scholar
  45. 45.
    Kallakury BV, Hartmann DP, Cossman J, Gootenberg JE, Bagg A (1999) Posttherapy surveillance of B-cell precursor acute lymphoblastic leukemia. Value of polymerase chain reaction and limitations of flow cytometry. Am J Clin Pathol 111(6):759–766PubMedGoogle Scholar
  46. 46.
    McKenna RW, Washington LT, Aquino DB, Picker LJ, Kroft SH (2001) Immunophenotypic analysis of hematogones (B-lymphocyte precursors) in 662 consecutive bone marrow specimens by 4-color flow cytometry. Blood 98(8):2498–2507PubMedGoogle Scholar
  47. 47.
    Muehleck SD, McKenna RW, Gale PF, Brunning RD (1983) Terminal deoxynucleotidyl transferase (TdT)-positive cells in bone marrow in the absence of hematologic malignancy. Am J Clin Pathol 79(3):277–284PubMedGoogle Scholar
  48. 48.
    Longacre TA, Foucar K, Crago S, Chen IM, Griffith B, Dressler L, McConnell TS, Duncan M, Gribble J (1989) Hematogones: a multiparameter analysis of bone marrow precursor cells. Blood 73(2):543–552PubMedGoogle Scholar
  49. 49.
    Chantepie SP, Salaun V, Parienti JJ, Truquet F, Macro M, Cheze S, Vilque JP, Reman O (2011) Hematogones: a new prognostic factor for acute myeloblastic leukemia. Blood 117(4):1315–1318PubMedGoogle Scholar
  50. 50.
    Honebrink T, Dayton V, Burke MJ, Larsen K, Cao Q, Brunstein C, Weisdorf D, Miller JS, Wagner JE, Verneris MR (2012) Impact of bone marrow hematogones on umbilical cord blood transplantation outcomes in patients with acute myeloid leukemia. Biol Blood Marrow Transplant 18(6):930–936PubMedGoogle Scholar
  51. 51.
    Christopeit M, Heiland A, Binder M, Zabelina T, Ayuk F, Horn C, Haferlach T, Bokemeyer C, Kröger N, Bacher U (2013) Impact of physiological BM CD10+CD19+ B-cell precursors (haematogones) in the post-transplant period in patients with AML. Bone Marrow Transplant 48(9):1257–1259PubMedGoogle Scholar
  52. 52.
    Shima T, Miyamoto T, Kikushige Y, Mori Y, Kamezaki K, Takase K, Henzan H, Numata A, Ito Y, Takenaka K, Iwasaki H, Kamimura T, Eto T, Nagafuji K, Teshima T, Kato K, Akashi K (2013) Quantitation of hematogones at the time of engraftment is a useful prognostic indicator in allogeneic hematopoietic stem cell transplantation. Blood 121(5):840–848PubMedGoogle Scholar
  53. 53.
    Barrios M, Jimenez-Velasco A, Roman-Gomez J, Madrigal ME, Castillejo JA, Torres A, Heiniger A (2003) Chimerism status is a useful predictor of relapse after allogeneic stem cell transplantation for acute leukemia. Haematologica 88(7):801–810PubMedGoogle Scholar
  54. 54.
    Fialkow PJ, Thomas ED, Bryant JI, Neiman PE (1971) Leukaemic transformation of engrafted human marrow cells in vivo. Lancet 1(7693):251–255PubMedGoogle Scholar
  55. 55.
    Niederwieser DW, Appelbaum FR, Gastl G, Gersdorf E, Meister B, Geissler D, Tratkiewicz JA, Thaler J, Huber C (1990) Inadvertent transmission of a donor's acute myeloid leukemia in bone marrow transplantation for chronic myelocytic leukemia. N Engl J Med 322(25):1794–1796PubMedGoogle Scholar
  56. 56.
    Thiede C (2004) Diagnostic chimerism analysis after allogeneic stem cell transplantation: new methods and markers. Am J Pharmacogenomics 4(3):177–187PubMedGoogle Scholar
  57. 57.
    Alizadeh M, Bernard M, Danic B, Dauriac C, Birebent B, Lapart C, Lamy T, Le Prise PY, Beauplet A, Bories D, Semana G, Quelvennec E (2002) Quantitative assessment of hematopoietic chimerism after bone marrow transplantation by real-time quantitative polymerase chain reaction. Blood 99(12):4618–4625PubMedGoogle Scholar
  58. 58.
    Fehse B, Chukhlovin A, Kuhlcke K, Marinetz O, Vorwig O, Renges H, Krüger W, Zabelina T, Dudina O, Finckenstein FG, Kröger N, Kabisch H, Hochhaus A, Zander AR (2001) Real-time quantitative Y chromosome-specific PCR (QYCS-PCR) for monitoring hematopoietic chimerism after sex-mismatched allogeneic stem cell transplantation. J Hematother Stem Cell Res 10(3):419–425PubMedGoogle Scholar
  59. 59.
    Lion T, Watzinger F, Preuner S, Kreyenberg H, Tilanus M, de Weger R, van Loon J, de Vries L, Cave H, Acquaviva C, Lawler M, Crampe M, Serra A, Saglio B, Colnaghi F, Biondi A, van Dongen JJ, van der Burg M, Gonzalez M, Alcoceba M, Barbany G, Hermanson M, Roosnek E, Steward C, Harvey J, Frommlet F, Bader P (2012) The EuroChimerism concept for a standardized approach to chimerism analysis after allogeneic stem cell transplantation. Leukemia 26(8):1821–1828PubMedGoogle Scholar
  60. 60.
    van der Burg M, Kreyenberg H, Willasch A, Barendregt BH, Preuner S, Watzinger F, Lion T, Roosnek E, Harvey J, Alcoceba M, Diaz MG, Bader P, van Dongen JJ, QLRT EU-sECp (2011) Standardization of DNA isolation from low cell numbers for chimerism analysis by PCR of short tandem repeats. Leukemia 25(9):1467–1470PubMedGoogle Scholar
  61. 61.
    Tobiasson M, Olsson R, Hellstrom-Lindberg E, Mattsson J (2011) Early detection of relapse in patients with myelodysplastic syndrome after allo-SCT. Bone Marrow Transplant 46(5):719–726PubMedGoogle Scholar
  62. 62.
    Rosenow F, Berkemeier A, Krug U, Müller-Tidow C, Gerss J, Silling G, Groth C, Wieacker P, Bogdanova N, Mesters R, Büchner T, Kienast J, Berdel WE, Stelljes M (2013) CD34(+) lineage specific donor cell chimerism for the diagnosis and treatment of impending relapse of AML or myelodysplastic syndrome after allo-SCT. Bone Marrow Transplant 48(8):1070–1076PubMedGoogle Scholar
  63. 63.
    Bornhäuser M, Oelschlaegel U, Platzbecker U, Bug G, Lutterbeck K, Kiehl MG, Schetelig J, Kiani A, Illmer T, Schaich M, Theuser C, Mohr B, Brendel C, Fauser AA, Klein S, Martin H, Ehninger G, Thiede C (2009) Monitoring of donor chimerism in sorted CD34+ peripheral blood cells allows the sensitive detection of imminent relapse after allogeneic stem cell transplantation. Haematologica 94(11):1613–1617PubMedCentralPubMedGoogle Scholar
  64. 64.
    Zeiser R, Spyridonidis A, Wasch R, Ihorst G, Grüllich C, Bertz H, Finke J (2005) Evaluation of immunomodulatory treatment based on conventional and lineage-specific chimerism analysis in patients with myeloid malignancies after myeloablative allogeneic hematopoietic cell transplantation. Leukemia 19(5):814–821PubMedGoogle Scholar
  65. 65.
    Platzbecker U, Wermke M, Radke J, Oelschlaegel U, Seltmann F, Kiani A, Klut IM, Knoth H, Rollig C, Schetelig J, Mohr B, Graehlert X, Ehninger G, Bornhäuser M, Thiede C (2012) Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia 26(3):381–389PubMedCentralPubMedGoogle Scholar
  66. 66.
    Schroeder T, Czibere A, Platzbecker U, Bug G, Uharek L, Luft T, Giagounidis A, Zohren F, Bruns I, Wolschke C, Rieger K, Fenk R, Germing U, Haas R, Kröger N, Kobbe G (2013) Azacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation. Leukemia 27(6):1229–1235PubMedGoogle Scholar
  67. 67.
    Hoffmann JC, Stabla K, Burchert A, Volkmann T, Bornhäuser M, Thiede C, Neubauer A, Brendel C (2014) Monitoring of acute myeloid leukemia patients after allogeneic stem cell transplantation employing semi-automated CD34+ donor cell chimerism analysis. Ann Hematol 93(2):279–285PubMedGoogle Scholar
  68. 68.
    Chapuis AG, Ragnarsson GB, Nguyen HN, Chaney CN, Pufnock JS, Schmitt TM, Duerkopp N, Roberts IM, Pogosov GL, Ho WY, Ochsenreither S, Wolfl M, Bar M, Radich JP, Yee C, Greenberg PD (2013) Transferred WT1-reactive CD8+ T cells can mediate antileukemic activity and persist in post-transplant patients. Sci Transl Med 5(174):174ra127Google Scholar
  69. 69.
    Schmitt TM, Aggen DH, Stromnes IM, Dossett ML, Richman SA, Kranz DM, Greenberg PD (2013) Enhanced-affinity murine T-cell receptors for tumor/self-antigens can be safe in gene therapy despite surpassing the threshold for thymic selection. Blood 122(3):348–356PubMedGoogle Scholar
  70. 70.
    Cilloni D, Renneville A, Hermitte F, Hills RK, Daly S, Jovanovic JV, Gottardi E, Fava M, Schnittger S, Weiss T, Izzo B, Nomdedeu J, van der Heijden A, van der Reijden BA, Jansen JH, van der Velden VH, Ommen H, Preudhomme C, Saglio G, Grimwade D (2009) Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: a European LeukemiaNet study. J Clin Oncol 27(31):5195–5201PubMedGoogle Scholar
  71. 71.
    Zhao XS, Jin S, Zhu HH, Xu LP, Liu DH, Chen H, Liu KY, Huang XJ (2012) Wilms' tumor gene 1 expression: an independent acute leukemia prognostic indicator following allogeneic hematopoietic SCT. Bone Marrow Transplant 47(4):499–507PubMedGoogle Scholar
  72. 72.
    Pozzi S, Geroldi S, Tedone E, Luchetti S, Grasso R, Colombo N, Di Grazia C, Lamparelli T, Gualandi F, Ibatici A, Bregante S, Van Lint MT, Raiola AM, Dominietto A, Varaldo R, Signori A, Bacigalupo A (2013) Leukaemia relapse after allogeneic transplants for acute myeloid leukaemia: predictive role of WT1 expression. Br J Haematol 160(4):503–509PubMedGoogle Scholar
  73. 73.
    Candoni A, Toffoletti E, Gallina R, Simeone E, Chiozzotto M, Volpetti S, Fanin R (2011) Monitoring of minimal residual disease by quantitative WT1 gene expression following reduced intensity conditioning allogeneic stem cell transplantation in acute myeloid leukemia. Clin Transplant 25(2):308–316PubMedGoogle Scholar
  74. 74.
    Dominietto A, Pozzi S, Miglino M, Albarracin F, Piaggio G, Bertolotti F, Grasso R, Zupo S, Raiola AM, Gobbi M, Frassoni F, Bacigalupo A (2007) Donor lymphocyte infusions for the treatment of minimal residual disease in acute leukemia. Blood 109(11):5063–5064PubMedGoogle Scholar
  75. 75.
    Macedo A, Orfao A, Gonzalez M, Vidriales MB, Lopez-Berges MC, Martinez A, San Miguel JF (1995) Immunological detection of blast cell subpopulations in acute myeloblastic leukemia at diagnosis: implications for minimal residual disease studies. Leukemia 9(6):993–998PubMedGoogle Scholar
  76. 76.
    Macedo A, Orfao A, Vidriales MB, Lopez-Berges MC, Valverde B, Gonzalez M, Caballero MD, Ramos F, Martinez M, Fernandez-Calvo J et al (1995) Characterization of aberrant phenotypes in acute myeloblastic leukemia. Ann Hematol 70(4):189–194PubMedGoogle Scholar
  77. 77.
    Kern W, Bacher U, Haferlach C, Schnittger S, Haferlach T (2010) The role of multiparameter flow cytometry for disease monitoring in AML. Best Pract Res Clin Haematol 23(3):379–390PubMedGoogle Scholar
  78. 78.
    Miyazaki T, Fujita H, Fujimaki K, Hosoyama T, Watanabe R, Tachibana T, Fujita A, Matsumoto K, Tanaka M, Koharazawa H, Taguchi J, Tomita N, Sakai R, Fujisawa S, Kanamori H, Ishigatsubo Y (2012) Clinical significance of minimal residual disease detected by multidimensional flow cytometry: serial monitoring after allogeneic stem cell transplantation for acute leukemia. Leuk Res 36(8):998–1003PubMedGoogle Scholar
  79. 79.
    Diez-Campelo M, Perez-Simon JA, Perez J, Alcoceba M, Richtmon J, Vidriales B, San Miguel J (2009) Minimal residual disease monitoring after allogeneic transplantation may help to individualize post-transplant therapeutic strategies in acute myeloid malignancies. Am J Hematol 84(3):149–152PubMedGoogle Scholar
  80. 80.
    Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G, Kantarjian H, Raza A, Levine RL, Neuberg D, Ebert BL (2011) Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 364(26):2496–2506PubMedCentralPubMedGoogle Scholar
  81. 81.
    Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, Sato Y, Sato-Otsubo A, Kon A, Nagasaki M, Chalkidis G, Suzuki Y, Shiosaka M, Kawahata R, Yamaguchi T, Otsu M, Obara N, Sakata-Yanagimoto M, Ishiyama K, Mori H, Nolte F, Hofmann WK, Miyawaki S, Sugano S, Haferlach C, Koeffler HP, Shih LY, Haferlach T, Chiba S, Nakauchi H, Miyano S, Ogawa S (2011) Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 478(7367):64–69PubMedGoogle Scholar
  82. 82.
    Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC, Wartman LD, Lamprecht TL, Liu F, Xia J, Kandoth C, Fulton RS, McLellan MD, Dooling DJ, Wallis JW, Chen K, Harris CC, Schmidt HK, Kalicki-Veizer JM, Lu C, Zhang Q, Lin L, O'Laughlin MD, McMichael JF, Delehaunty KD, Fulton LA, Magrini VJ, McGrath SD, Demeter RT, Vickery TL, Hundal J, Cook LL, Swift GW, Reed JP, Alldredge PA, Wylie TN, Walker JR, Watson MA, Heath SE, Shannon WD, Varghese N, Nagarajan R, Payton JE, Baty JD, Kulkarni S, Klco JM, Tomasson MH, Westervelt P, Walter MJ, Graubert TA, DiPersio JF, Ding L, Mardis ER, Wilson RK (2012) The origin and evolution of mutations in acute myeloid leukemia. Cell 150(2):264–278PubMedCentralPubMedGoogle Scholar
  83. 83.
    Jan M, Snyder TM, Corces-Zimmerman MR, Vyas P, Weissman IL, Quake SR, Majeti R (2012) Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Transl Med 4(149):149ra118PubMedCentralPubMedGoogle Scholar
  84. 84.
    Leroy H, de Botton S, Grardel-Duflos N, Darre S, Leleu X, Roumier C, Morschhauser F, Lai JL, Bauters F, Fenaux P, Preudhomme C (2005) Prognostic value of real-time quantitative PCR (RQ-PCR) in AML with t(8;21). Leukemia 19(3):367–372PubMedGoogle Scholar
  85. 85.
    Schnittger S, Kern W, Tschulik C, Weiss T, Dicker F, Falini B, Haferlach C, Haferlach T (2009) Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML. Blood 114(11):2220–2231PubMedGoogle Scholar
  86. 86.
    Sockel K, Wermke M, Radke J, Kiani A, Schaich M, Bornhäuser M, Ehninger G, Thiede C, Platzbecker U (2011) Minimal residual disease-directed preemptive treatment with azacitidine in patients with NPM1-mutant acute myeloid leukemia and molecular relapse. Haematologica 96(10):1568–1570PubMedCentralPubMedGoogle Scholar
  87. 87.
    Shayegi N, Kramer M, Bornhäuser M, Schaich M, Schetelig J, Platzbecker U, Röllig C, Heiderich C, Landt O, Ehninger G, Thiede C, Study Alliance L (2013) The level of residual disease based on mutant NPM1 is an independent prognostic factor for relapse and survival in AML. Blood 122(1):83–92PubMedGoogle Scholar
  88. 88.
    Matsuda K, Ishida F, Ito T, Nakazawa H, Miura S, Taira C, Sueki A, Kobayashi Y, Honda T (2012) Spliceosome-related gene mutations in myelodysplastic syndrome can be used as stable markers for monitoring minimal residual disease during follow-up. Leuk Res 36(11):1393–1397PubMedGoogle Scholar
  89. 89.
    Scholl S, Krause C, Loncarevic IF, Müller R, Kunert C, Wedding U, Sayer HG, Clement JH, Höffken K (2005) Specific detection of Flt3 point mutations by highly sensitive real-time polymerase chain reaction in acute myeloid leukemia. J Lab Clin Med 145(6):295–304PubMedGoogle Scholar
  90. 90.
    Kohlmann A, Grossmann V, Harbich S, Dicker F, Alpermann T, Nadarajah N, Kern W, Haferlach C, Haferlach T, Schnittger S (2011) Monitoring of minimal residual disease using next-generation deep-sequencing in 460 acute myeloid leukemia cases identifies RUNX1 mutated patients with resistant disease. Blood 118(21):340–340Google Scholar
  91. 91.
    Fang M, Storer B, Wood B, Gyurkocza B, Sandmaier BM, Appelbaum FR (2012) Prognostic impact of discordant results from cytogenetics and flow cytometry in patients with acute myeloid leukemia undergoing hematopoietic cell transplantation. Cancer 118(9):2411–2419PubMedCentralPubMedGoogle Scholar
  92. 92.
    Kwon M, Martinez-Laperche C, Infante M, Carretero F, Balsalobre P, Serrano D, Gayoso J, Perez-Corral A, Anguita J, Diez-Martin JL, Buno I (2012) 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 18(8):1235–1242PubMedGoogle Scholar
  93. 93.
    Lange T, Hubmann M, Burkhardt R, Franke GN, Cross M, Scholz M, Leiblein S, Al-Ali HK, Edelmann J, Thiery J, Niederwieser D (2011) Monitoring of WT1 expression in PB and CD34(+) donor chimerism of BM predicts early relapse in AML and MDS patients after hematopoietic cell transplantation with reduced-intensity conditioning. Leukemia 25(3):498–505PubMedGoogle Scholar
  94. 94.
    Bacher U, Kern W, Schoch C, Schnittger S, Hiddemann W, Haferlach T (2006) Evaluation of complete disease remission in acute myeloid leukemia: a prospective study based on cytomorphology, interphase fluorescence in situ hybridization, and immunophenotyping during follow-up in patients with acute myeloid leukemia. Cancer 106(4):839–847PubMedGoogle Scholar
  95. 95.
    Mancini M, Cedrone M, Diverio D, Emanuel B, Stul M, Vranckx H, Brama M, De Cuia MR, Nanni M, Fazi F, Mecucci C, Alimena G, Hagemeijer A (2000) Use of dual-color interphase FISH for the detection of inv(16) in acute myeloid leukemia at diagnosis, relapse and during follow-up: a study of 23 patients. Leukemia 14(3):364–368PubMedGoogle Scholar
  96. 96.
    Zhao XS, Yan CH, Liu DH, Xu LP, Liu YR, Liu KY, Qin YZ, Wang Y, Huang XJ (2013) Combined use of WT1 and flow cytometry monitoring can promote sensitivity of predicting relapse after allogeneic HSCT without affecting specificity. Ann Hematol 92(8):1111–1119PubMedGoogle Scholar
  97. 97.
    Bacigalupo A, Van Lint MT, Occhini D, Gualandi F, Lamparelli T, Sogno G, Tedone E, Frassoni F, Tong J, Marmont AM (1991) Increased risk of leukemia relapse with high-dose cyclosporine A after allogeneic marrow transplantation for acute leukemia. Blood 77(7):1423–1428PubMedGoogle Scholar
  98. 98.
    Locatelli F, Zecca M, Rondelli R, Bonetti F, Dini G, Prete A, Messina C, Uderzo C, Ripaldi M, Porta F, Giorgiani G, Giraldi E, Pession A (2000) Graft versus host disease prophylaxis with low-dose cyclosporine-A reduces the risk of relapse in children with acute leukemia given HLA-identical sibling bone marrow transplantation: results of a randomized trial. Blood 95(5):1572–1579PubMedGoogle Scholar
  99. 99.
    Bacigalupo A, Lamparelli T, Gualandi F, Bregante S, Raiola A, di Grazia C, Dominietto A, Romagnani C, Occhini D, Frassoni F, van Lint MT (2001) Increased risk of leukemia relapse with high dose cyclosporine after allogeneic marrow transplantation for acute leukemia: 10 year follow-up of a randomized study. Blood 98(10):3174–3175Google Scholar
  100. 100.
    Schmid C, Labopin M, Nagler A, Bornhäuser M, Finke J, Fassas A, Volin L, Gurman G, Maertens J, Bordigoni P, Holler E, Ehninger G, Polge E, Gorin NC, Kolb HJ, Rocha V, Party EALW (2007) Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol 25(31):4938–4945PubMedGoogle Scholar
  101. 101.
    Levine JE, Braun T, Penza SL, Beatty P, Cornetta K, Martino R, Drobyski WR, Barrett AJ, Porter DL, Giralt S, Leis J, Holmes HE, Johnson M, Horowitz M, Collins RH Jr (2002) Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation. J Clin Oncol 20(2):405–412PubMedGoogle Scholar
  102. 102.
    Metzelder S, Wang Y, Wollmer E, Wanzel M, Teichler S, Chaturvedi A, Eilers M, Enghofer E, Neubauer A, Burchert A (2009) Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood 113(26):6567–6571PubMedGoogle Scholar
  103. 103.
    Metzelder SK, Schroeder T, Finck A, Scholl S, Fey M, Gotze K, Linn YC, Kröger M, Reiter A, Salih HR, Heinicke T, Stuhlmann R, Müller L, Giagounidis A, Meyer RG, Brugger W, Vohringer M, Dreger P, Mori M, Basara N, Schafer-Eckart K, Schultheis B, Baldus C, Neubauer A, Burchert A (2012) High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. Leukemia 26(11):2353–2359PubMedGoogle Scholar
  104. 104.
    Wermke M, Thiede C, Kiani A, Ehninger G, Bornhäuser M, Platzbecker U (2010) Successful treatment of molecular relapse in NPM1-positive AML using 5-azacytidine. Leukemia 24(1):236–237PubMedGoogle Scholar
  105. 105.
    Kawahara M, Pandolfi A, Bartholdy B, Barreyro L, Will B, Roth M, Okoye-Okafor UC, Todorova TI, Figueroa ME, Melnick A, Mitsiades CS, Steidl U (2012) H2.0-like homeobox regulates early hematopoiesis and promotes acute myeloid leukemia. Cancer Cell 22(2):194–208PubMedCentralPubMedGoogle Scholar
  106. 106.
    Figueroa ME, Lugthart S, Li Y, Erpelinck-Verschueren C, Deng X, Christos PJ, Schifano E, Booth J, van Putten W, Skrabanek L, Campagne F, Mazumdar M, Greally JM, Valk PJ, Löwenberg B, Delwel R, Melnick A (2010) DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 17(1):13–27PubMedCentralPubMedGoogle Scholar
  107. 107.
    Bartholdy B, Christopeit M, Will B, Mo Y, Barreyro L, Yu Y, Bhagat TD, Okoye-Okafor UC, Todorova TI, Greally JM, Levine RL, Melnick A, Verma A, Steidl U (2014) HSC commitment–associated epigenetic signature is prognostic in acute myeloid leukemia. J Clin Invest 124(3):1158–1167Google Scholar
  108. 108.
    Pulikkan JA, Peramangalam PS, Dengler V, Ho PA, Preudhomme C, Meshinchi S, Christopeit M, Nibourel O, Müller-Tidow C, Bohlander SK, Tenen DG, Behre G (2010) C/EBPalpha regulated microRNA-34a targets E2F3 during granulopoiesis and is down-regulated in AML with CEBPA mutations. Blood 116(25):5638–5649PubMedCentralPubMedGoogle Scholar
  109. 109.
    Marcucci G, Maharry KS, Metzeler KH, Volinia S, Wu YZ, Mrozek K, Nicolet D, Kohlschmidt J, Whitman SP, Mendler JH, Schwind S, Becker H, Eisfeld AK, Carroll AJ, Powell BL, Kolitz JE, Garzon R, Caligiuri MA, Stone RM, Bloomfield CD (2013) Clinical role of microRNAs in cytogenetically normal acute myeloid leukemia: miR-155 upregulation independently identifies high-risk patients. J Clin Oncol 31(17):2086–2093PubMedGoogle Scholar
  110. 110.
    Grasedieck S, Sorrentino A, Langer C, Buske C, Döhner H, Mertens D, Kuchenbauer F (2013) Circulating microRNAs in hematological diseases: principles, challenges, and perspectives. Blood 121(25):4977–4984PubMedGoogle Scholar
  111. 111.
    DiNardo CD, Propert KJ, Loren AW, Paietta E, Sun Z, Levine RL, Straley KS, Yen K, Patel JP, Agresta S, Abdel-Wahab O, Perl AE, Litzow MR, Rowe JM, Lazarus HM, Fernandez HF, Margolis DJ, Tallman MS, Luger SM, Carroll M (2013) Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia. Blood 121(24):4917–4924PubMedGoogle Scholar
  112. 112.
    Gonen M, Sun Z, Figueroa ME, Patel JP, Abdel-Wahab O, Racevskis J, Ketterling RP, Fernandez H, Rowe JM, Tallman MS, Melnick A, Levine RL, Paietta E (2012) CD25 expression status improves prognostic risk classification in AML independent of established biomarkers: ECOG phase 3 trial, E1900. Blood 120(11):2297–2306PubMedCentralPubMedGoogle Scholar
  113. 113.
    Barreyro L, Will B, Bartholdy B, Zhou L, Todorova TI, Stanley RF, Ben-Neriah S, Montagna C, Parekh S, Pellagatti A, Boultwood J, Paietta E, Ketterling RP, Cripe L, Fernandez HF, Greenberg PL, Tallman MS, Steidl C, Mitsiades CS, Verma A, Steidl U (2012) Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS. Blood 120(6):1290–1298PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of Cell BiologyAlbert Einstein College of MedicineThe BronxUSA
  2. 2.Department for Stem Cell TransplantationUniversity of HamburgHamburgGermany
  3. 3.MLL Munich Leukemia LaboratoryMunichGermany

Personalised recommendations