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Acute Leukemia

Quantitative chimerism: an independent acute leukemia prognosis indicator following allogeneic hematopoietic SCT

Bone Marrow Transplantation volume 49, pages 1269–1277 (2014)Cite this article

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Abstract

This study evaluates the prognostic significance of quantitative chimerism to monitor minimal residual disease and predict relapse in acute leukemia (AL) patients following allogeneic hematopoietic SCT (HSCT). The quantitative chimerism levels of 129 AL patients were measured using RQ-PCR based on 29 sequence polymorphisms. Receiver-operating characteristic curve indicated that the optimal cutoff point to predict an inevitable relapse was 1.0%, which results in 100.0% sensitivity and 79.6% specificity.The relapse rate of patients with chimerism >1.0% at 2 years was 55.0%, whereas that for patients with chimerism <1.0% was 0%(P=0.000). Quantitative chimerism >1.00% indicated a higher probability of relapse. Cox multivariate analysis indicated that quantitative chimerism >1.00% was associated with lower disease-free survival (hazard ratio (HR)=10.825; 95% confidence interval (CI) =4.704–24.912, P=0.000) and lower OS (HR=8.681; 95% CI=3.728–20.212, P=0.000). Patients (24/47 with quantitative chimerism >1.00%) who received preemptive modified DLI immunotherapy had significantly lower relapse rate (37.5%) than those (n=9) who did not (100%; P=0.001). Thus, quantitative chimerism is an independent prognostic factor that predicts clinical outcomes after HSCT and provides a guide for suitable interventions.

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References

  1. Mortimer J, Blinder MA, Schulman S, Appelbaum FR, Buckner CD, Clift RA et al. Relapse of acute leukemia after marrow transplantation:natural history and results of subsequent therapy. J Clin Oncol 1989; 7: 50–57.

    Article  CAS  PubMed  Google Scholar 

  2. Frassoni F, Barrett AJ, Grañena A, Ernst P, Garthon G, Kolb HJ et al. Relapse after allogeneic bone marrow transplantation for acute leukaemia: a survey by the E.B.M. T. of 117 cases. Br J Haematol 1988; 70: 317–320.

    CAS  PubMed  Google Scholar 

  3. Deol A, Lum LG . Role of donor lymphocyte infusions in relapsed hematological malignancies after stem cell transplantation revisited. Cancer Treat Rev 2010; 36: 528–538.

    PubMed  PubMed Central  Google Scholar 

  4. Bader P, Kreyenberg H, Hoelle W, Dueckers G, Kremens B, Dilloo D et al. Increasing mixed chimerism defines a high-risk group of childhood acute myelogenous leukemia patients after allogeneic stem cell transplantation where pre-emptive immunotherapy may be effective. Bone Marrow Transplant 2004; 33: 815–821.

    Article  CAS  PubMed  Google Scholar 

  5. Kreyenberg H, Holle W, Mohrle S, Niethammer D, Bader P . Quantitative analysis of chimerism after allogeneic stem cell transplantation by PCR amplification of microsatellite markers and capillary electrophoresis with fluorescence detection: the Tuebingen experience. Leukemia 2003; 17: 237–240.

    Article  CAS  PubMed  Google Scholar 

  6. Bader P, Klingebiel T, Schaudt A, Theurer-Mainka U, Handgretinger R, Lang P et al. Prevention of relapse in pediatric patients with acute leukemias and MDS after allogeneic SCT by early immunotherapy initiated on the basis of increasing mixed chimerism: a single center experience of 12 children. Leukemia 1999; 13: 2079–2086.

    Article  CAS  PubMed  Google Scholar 

  7. Bader P, Beck J, Schlegel PG, Handgretinger R, Niethammer D, Klingebiel T . Additional immunotherapy on the basis of increasing mixed hematopoietic chimerism after allogeneic BMT in children with acute leukemia: is there an option to prevent relapse? Bone Marrow Transplant 1997; 20: 79–81.

    Article  CAS  PubMed  Google Scholar 

  8. Beck JF, Klingebiel T, Kreyenberg H, Schaudt A, Wölle W, Niethammer D et al. Relapse of childhood ALL, AML and MDS after allogeneic stem cell transplantation can be prevented by donor lymphocyte infusion in a critical stage of increasing mixed chimerism [Article in German]. Klin Padiatr 2002; 214: 201–205.

    Article  CAS  PubMed  Google Scholar 

  9. Porter DL, Antin JH . Donor leukocyte infusions in myeloid malignancies: new strategies. Best Pract Res Clin Haematol 2006; 19: 737–755.

    Article  CAS  PubMed  Google Scholar 

  10. Locatelli F, Zecca M, Rondelli R, Bonetti F, Dini G, Prete A et al. 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 2000; 95: 1572–1579.

    CAS  PubMed  Google Scholar 

  11. Cheson BD, Bennett JM, Kopecky KJ, Büchner 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 

  12. Horn B, Soni S, Khan S, Petrovic A, Breslin N, Cowan M et al. Feasibility study of preemptive withdrawal of immunosuppression based on chimerism testing in children undergoing myeloablative allogeneic transplantation for hematologic malignancies. Bone Marrow Transplant 2009; 43: 469–476.

    Article  CAS  PubMed  Google Scholar 

  13. Formánková R, Sedlacek P, Krsková L, Ríhová H, Srámková L, Star J . Chimerism-directed adoptive immunotherapy in prevention and treatment of post-transplant relapse of leukemia in childhood. Haematologica 2003; 88: 117–118.

    PubMed  Google Scholar 

  14. Formánková R, Honzatkova L, Sieglova Z, Starý J, Sedlácek P, Brdicka R . Detailed monitoring of hematopoietic chimerism in a child treated by adoptive immunotherapy for high risk of relapse after BMT for acute myeloid leukemia. Bone Marrow Transplant 2000; 25: 453–456.

    Article  PubMed  Google Scholar 

  15. Alizadeh M, Bernard M, Danic B, Dauriac C, Birebent B, Lapart C et al. Quantitative assessment of hematopoietic chimerism after bone marrow transplantation by real-time quantitative polymerase chain reaction. Blood 2002; 99: 4618–4625.

    Article  CAS  PubMed  Google Scholar 

  16. Maas F, Schaap N, Kolen S, Zoetbrood A, Buño I, Dolstra H et al. Quantification of donor and recipient hemopoietic cells by real-time PCR of single nucleotide polymorphisms. Leukemia 2003; 17: 621–629.

    Article  CAS  PubMed  Google Scholar 

  17. Maas F, Schaap N, Kolen S, Zoetbrood A, Buño I, Dolstra H et al. Quantification of donor and recipient hemopoietic cells by real-time PCR of single nucleotide polymorphisms. Leukemia 2003; 17: 630–633.

    Article  CAS  PubMed  Google Scholar 

  18. Maas F, Schaap N, Kolen S, Zoetbrood A, Buño I, Dolstra H et al. Corrigendum quantification of donor and recipient hemopoietic cells by real-time PCR of single nucleotide polymorphisms. Leukemia 2004; 18: 663.

    Article  CAS  Google Scholar 

  19. Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W et al. Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant 2006; 38: 291–297.

    Article  PubMed  Google Scholar 

  20. Chang YJ, Huang XJ . Haploidentical hematopoietic stem cell transplantation with unmanipulated granulocyte colony stimulating factor mobilized marrow and blood grafts. Curr Opin Hematol 2012; 19: 454–461.

    Article  CAS  PubMed  Google Scholar 

  21. Chang YJ, Huang XJ . Haploidentical bone marrow transplantation without T-cell depletion. Semin Oncol 2012; 39: 653–663.

    Article  PubMed  Google Scholar 

  22. Qin XY, Li GX, Qin YZ, Wang Y, Wang FR, Liu DH et al. Quantitative assessment of hematopoietic chimerism after hematopoietic stem cell transplantation by quantitative real-time polymerase chain reaction of sequence polymorphism systems. Chin Med J 2011; 124: 2301–2308.

    CAS  PubMed  Google Scholar 

  23. Qin XY, Li GX, Qin YZ, Wang Y, Wang FR, Liu DH et al. Quantitative chimerism kinetics in relapsed leukemia patients after allogeneic hematopoietic stem cell transplantation. Chin Med J 2012; 125: 1952–1959.

    PubMed  Google Scholar 

  24. Zhao XS, Liu YR, Zhu HH, Xu LP, Liu DH, Liu KY et al. Monitoring MRD with flow cytometry: an effective method to predict relapse for ALL patients after allogeneic hematopoietic stem cell transplantation. Ann Hematol 2012; 91: 183–192.

    Article  CAS  PubMed  Google Scholar 

  25. Zhao XS, Jin S, Zhu HH, Xu LP, Liu DH, Chen H et al. Wilms’ tumor gene1 expression: an independent acute leukemia prognostic indicator following allogeneic hematopoietic SCT. Bone Marrow Transplant 2012; 47: 499–507.

    Article  CAS  PubMed  Google Scholar 

  26. Cancer Therapy Evaluation Program. NCI CommonTerminology Criteria for Adverse Events (CTCAE)v4.0. http://www.ctep.cancer.gov (published 28 May 2009).

  27. Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W . Donor lymphocyte infusion for the treatment of leukemia relapse after HLA-mismatched/haploidentical T-cell-replete hematopoietic stem cell transplantation. Haematologica 2007; 92: 414–417.

    Article  PubMed  Google Scholar 

  28. Huang XJ, Liu DH, Xu LP, Chen H, Han W, Liu KY et al. Prophylactic infusion ofdonor granulocyte colony stimulating factor mobilized peripheral blood progenitor cells after allogeneic hematological stem cell transplantation in patients with high-risk leukemia. Leukemia 2006; 20: 365–368.

    Article  CAS  PubMed  Google Scholar 

  29. Huang XJ, Liu DH, Liu KY, Xu LP, Chen YH, Wang Y et al. Modified donor lymphocyte infusion after HLA-mismatched/haploidentical T cell-replete hematopoietic stem cell transplantation for prophylaxis of relapse of leukemia inpatients with advanced leukemia. J Clin Immunol 2008; 28: 276–283.

    Article  CAS  PubMed  Google Scholar 

  30. Yan CH, Liu DH, Liu KY, Xu LP, Liu YR, Chen H et al. Risk stratification-directed donor lymphocyte infusion could reduce relapse of standard-risk acute leukemia patients after allogeneic hematopoietic stem cell transplantation. Blood 2012; 119: 3256–3262.

    Article  CAS  PubMed  Google Scholar 

  31. Bader P, Kreyenberg H, Hoelle W, Dueckers G, Handgretinger R, Lang P et al. Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem-cell transplantation: possible role for pre-emptive immunotherapy? J Clin Oncol 2004; 22: 1696–1705.

    Article  PubMed  Google Scholar 

  32. Rettinger E, Willasch AM, Kreyenberg H, Borkhardt A, Holter W, Kremens B et al. Preemptive immunotherapy in childhood acute myeloid leukemia for patients showing evidence of mixed chimerism after allogeneic stem cell transplantation. Blood 2011; 118: 5681–5688.

    Article  CAS  PubMed  Google Scholar 

  33. Bader P, Beck J, Frey A, Schlegel PG, Hebarth H, Handgretinger R et al. Serial and quantitative analysis of mixed hematopoietic chimerism by PCR in patients with acute leukemias allows the prediction of relapse after allogeneic BMT. Bone Marrow Transplant 1998; 21: 487–495.

    Article  CAS  PubMed  Google Scholar 

  34. Pulsipher MA, Bader P, Klingebiel T, Cooper LJ . Allogeneic transplantation for pediatric acute lymphoblastic leukemia: the emerging role of peritransplantation minimal residual disease/chimerism monitoring and novel chemotherapeutic, molecular, and immune approaches aimed at preventing relapse. Biol Blood Marrow Transplant 2009; 15: 62–71.

    Article  PubMed  Google Scholar 

  35. Wiedemann B, Klyuchnikov E, Kröger N, Zabelina T, Stahl T, Zeschke S et al. Chimerism studies with quantitative real-time PCR in stem cell recipients with acute myeloid leukemia. Exp Hematol 2010; 38: 1261–1271.

    Article  CAS  PubMed  Google Scholar 

  36. Koldehoff M, Steckel NK, Hlinka M, Beelen DW, Elmaagacli AH . Quantitative analysis of chimerism after allogeneic stem cell transplantation by real-time polymerase chain reaction with single nucleotide polymorphisms, standard tandem repeats, and Y-chromosome-Specific sequences. Am J Hematol 2006; 81: 735–746.

    Article  CAS  PubMed  Google Scholar 

  37. Chen DP, Tseng CP, Wang WT, Wang MC, Tsai SH, Sun CF . Real-time biallelic polymorphism-polymerase chain reaction for chimerism monitoring of hematopoietic stem cell transplantation relapsed patients. Clin Chim Acta 2011; 412: 625–630.

    Article  CAS  PubMed  Google Scholar 

  38. Horky O, Mayer J, Kablaskova L, Razga F, Krejci M, Kissova J et al. Increasing hematopoietic microchimerism is a reliable indicator of incipient AML relapse. Int J Lab Hematol 2011; 33: 57–66.

    Article  CAS  PubMed  Google Scholar 

  39. Willasch A, Schneider G, Reincke BS, Shayegi N, Kreyenberg H, Kuci S et al. Sequence polymorphism systems for quantitative real-time polymerase chain reaction to characterize hematopoietic chimerism—high informativity and sensitivity as well as excellent reproducibility and precision of measurement. Lab Hematol 2007; 13: 73–84.

    Article  CAS  PubMed  Google Scholar 

  40. Collins RH Jr, Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 1997; 15: 433–444.

    Article  PubMed  Google Scholar 

  41. Dazzi F, Szydlo RM, Cross NCP, Craddock C, Kaeda J, Kanfer E et al. Durability of responses following donor lymphocyte infusionsfor patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood 2000; 96: 2712–2716.

    CAS  PubMed  Google Scholar 

  42. Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, Arcese W et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 1995; 86: 2041–2050.

    CAS  PubMed  Google Scholar 

  43. Huang XJ, Wang Y, Liu DH, Xu LP, Liu KY, Chen H et al. Administration of short-term immunosuppressive agents after DLI reduces the incidence of DLI-associated acute GVHD without influencing the GVL effect. Bone Marrow Transplant 2009; 44: 309–316.

    Article  CAS  PubMed  Google Scholar 

  44. Huang X, Guo N, Ren H, Zhang Y, Gao Z, Lu D . An improved anti-leukemic effect achieved with donor progenitor cell infusion for relapse patients after allogeneic bonemarrow transplantation. Chin Med J (Engl) 2003; 116: 736–741.

    Google Scholar 

  45. Kröger N, Miyamura K, Bishop MR . Minimal residual disease following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2011; 17: S94–S100.

    Article  PubMed  Google Scholar 

  46. Qin Y, Zhu H, Jiang B, Li J, Lu X, Li L et al. Expression patterns of WT1 and PRAME in acute myeloid leukemia patients and their usefulness for monitoring minimal residual disease. Leuk Res 2009; 33: 384–390.

    Article  CAS  PubMed  Google Scholar 

  47. Yang L, Han Y, Suarez Saiz F, Minden MD . A tumor suppressor and oncogene: the WT1 story. Leukemia 2007; 21: 868–876.

    Article  CAS  PubMed  Google Scholar 

  48. Huang XJ, Guo NL, Ren HY, Zhang YC, Gao ZY, Xu LP et al. The comparison of GVL effects between the patients receiving donor peripheral blood stem cells and donor lymphocytes after allogeneic bone marrow transplantation. J Peking University (Health Sci) 2003; 35: 103–107.

    Google Scholar 

  49. Huang XJ, Chang YJ, Zhao XY . Maintaining hyporesponsiveness and polarization potential of T cells after in vitro mixture of G-CSF mobilized peripheral blood grafts and G-CSF primed bone marrow grafts in different proportions. Transpl Immunol 2007; 17: 193–197.

    Article  CAS  PubMed  Google Scholar 

  50. Jun HX, Jun CY, Yu ZX . In vivo induction of T-cell hyporesponsiveness and alteration of immunological cells of bone marrow grafts using granulocyte colony-stimulating factor. Haematologica 2004; 89: 1517–1524.

    CAS  PubMed  Google Scholar 

  51. Morris ES, Macdonald KP, Rowe V, Banovic T, Kuns RD, Don AL et al. NKT cell-dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs. J Clin Invest 2005; 115: 3093–3103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Levine JE, Braun T, Penza SL, Beatty P, Cornetta K, Martino R et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation. J Clin Oncol 2002; 20: 405–412.

    Article  CAS  PubMed  Google Scholar 

  53. Mackinnon S, Papadopoulos EB, Carabasi MH, Reich L, Collins NH, Boulad F et al. Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease. Blood 1995; 86: 1261–1268.

    CAS  PubMed  Google Scholar 

  54. Giralt S, Hester J, Huh Y, Hirsch-Ginsberg C, Rondon G, Seong D et al. CD8-depleteddonor lymphocyte infusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation. Blood 1995; 86: 4337–4343.

    CAS  PubMed  Google Scholar 

  55. Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, Ruggieri L et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 1997; 276: 1719–1724.

    Article  CAS  PubMed  Google Scholar 

  56. Alyea EP, Soiffer RJ, Canning C, Neuberg D, Schlossman R, Pickett C et al. Toxicity and efficacy of defined doses of CD4(t) donor lymphocytes for treatment of relapse after allogeneic bone marrow transplant. Blood 1998; 91: 3671–3680.

    CAS  PubMed  Google Scholar 

  57. Wehler TC, Nonn M, Brandt B, Britten CM, Grone M, Todorova M et al. Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines. Blood 2007; 109: 365–373.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Key Program of National Natural Science Foundation of China (Grant81230013), National Natural Science Foundation of China (Grant81170483), Beijing Municipal Science & Technology Commission (No.Z121107002612035) and Scientific Research Foundation for Capital Medicine Development (2011-4022-08).

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Authors and Affiliations

  1. Peking University People’s Hospital, Peking University Institute of Hematology, Beijing, China,

    X-Y Qin, G-X Li, Y-Z Qin, Y Wang, F-R Wang, D-H Liu, L-P Xu, H Chen, W Han, J-Z Wang, X-H Zhang, J-L Li, L-D Li, K-Y Liu & X-J Huang

  2. Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China

    X-Y Qin, G-X Li, Y-Z Qin, Y Wang, F-R Wang, D-H Liu, L-P Xu, H Chen, W Han, J-Z Wang, X-H Zhang, J-L Li, L-D Li, K-Y Liu & X-J Huang

  3. Peking-Tsinghua Center for Life Sciences, Beijing, China

    X-J Huang

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Qin, XY., Li, GX., Qin, YZ. et al. Quantitative chimerism: an independent acute leukemia prognosis indicator following allogeneic hematopoietic SCT. Bone Marrow Transplant 49, 1269–1277 (2014). https://doi.org/10.1038/bmt.2014.158

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