Abstract
Relapse of malignant disease remains the major complication in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after hematopoietic cell transplantation (HCT) with reduced-intensity conditioning (RIC). In this study, we investigated the predictive value of disease-specific markers (DSMs), donor chimerism (DC) analysis of unsorted (UDC) or CD34+ sorted cells and Wilms’ tumor gene 1 (WT1) expression. Eighty-eight patients with AML or MDS were monitored after allogenic HCT following 2 Gy total-body irradiation with (n=84) or without (n=4) fludarabine 3 × 30 mg/m2, followed by cyclosporin A and mycophenolate mofetil. DSMs were determined by fluorescence in situ hybridization (FISH) and WT1 expression by real-time polymerase chain reaction. Chimerism analysis was performed on unsorted or CD34+ sorted cells, by FISH or short tandem repeat polymerase chain reaction. Twenty-one (24%) patients relapsed within 4 months after HCT. UDC, CD34+ DC and WT1 expression were each significant predictors of relapse with sensitivities ranging from 53 to 79% and specificities of 82–91%. Relapse within 28 days was excluded almost entirely on the basis of WT1 expression combined with CD34+ DC kinetics. Monitoring of WT1 expression and CD34+ DC predict relapse of AML and MDS after RIC-HCT.
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References
Storb R . Can reduced-intensity allogeneic transplantation cure older adults with AML? Best Pract Res Clin Haematol 2007; 20: 85–90.
Niederwieser D, Lange T, Cross M, Basara N, Al-Ali H . Reduced intensity conditioning (RIC) haematopoietic cell transplants in elderly patients with AML. Best Pract Res Clin Haematol 2006; 19: 825–838.
Tauro S, Craddock C, Peggs K, Begum G, Mahendra P, Cook G et al. Allogeneic stem-cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and long-term disease-free survival in patients with high-risk acute myeloid leukemia and myelodysplasia. J Clin Oncol 2005; 23: 9387–9393.
Hallemeier CL, Girgis MD, Blum WG, Brown RA, Khoury HJ, Devine SM et al. Long-term remissions in patients with myelodysplastic syndrome and secondary acute myelogenous leukemia undergoing allogeneic transplantation following a reduced intensity conditioning regimen of 550 cGy total body irradiation and cyclophosphamide. Biol Blood Marrow Transplant 2006; 12: 749–757.
Schmid C, Schleuning M, Schwerdtfeger R, Hertenstein B, Mischak-Weissinger E, Bunjes D et al. Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood 2006; 108: 1092–1099.
Hegenbart U, Niederwieser D, Sandmaier BM, Maris MB, Shizuru JA, Greinix H et al. Treatment for acute myelogenous leukemia by low-dose, total-body, irradiation-based conditioning and hematopoietic cell transplantation from related and unrelated donors. J Clin Oncol 2006; 24: 444–453.
Al-Ali HK, Nehring C, Krahl R, Becker C, Leiblein S, Edelmann J et al. Donor CD34+ cell chimerism at day 28 and chronic graft-versus-host disease (GvHD) but not high-risk cytogenetics influence outcome of allogeneic hematopoetic cell transplantation (HCT) following reduced intensity conditioning (RIC) in patients with AML and MDS. ASH Annual Meeting Abstracts 2006; 108: 547.
Mielcarek M, Martin PJ, Maloney DG, Storb R, Sandmaier BM . Outcomes among patients with recurrent high-risk hematologic malignancy after nonmyeloablative versus myeloablative allogeneic hematopoietic cell transplantation. ASH Annual Meeting Abstracts 2006; 108: 262.
Lange T, Deininger M, Brand R, Hegenbart U, Al-Ali H, Krahl R et al. BCR-ABL transcripts are early predictors for hematological relapse in chronic myeloid leukemia after hematopoietic cell transplantation with reduced intensity conditioning. Leukemia 2004; 18: 1468–1475.
Kern W, Schoch C, Haferlach T, Schnittger S . Monitoring of minimal residual disease in acute myeloid leukemia. Crit Rev Oncol Hematol 2005; 56: 283–309.
Gozzetti A, Le Beau MM . Fluorescence in situ hybridization: uses and limitations. Semin Hematol 2000; 37: 320–333.
Thiede C . Diagnostic chimerism analysis after allogeneic stem cell transplantation: new methods and markers. Am J Pharmacogenom 2004; 4: 177–187.
Dohner K, Schlenk RF, Habdank M, Scholl C, Rucker FG, Corbacioglu A et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 2005; 106: 3740–3746.
Gorello P, Cazzaniga G, Alberti F, Dell’Oro MG, Gottardi E, Specchia G et al. Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations. Leukemia 2006; 20: 1103–1108.
Schnittger S, Schoch C, Kern W, Hiddemann W, Haferlach T . FLT3 length mutations as marker for follow-up studies in acute myeloid leukaemia. Acta Haematol 2004; 112: 68–78.
Scholl S, Krause C, Loncarevic IF, Muller R, Kunert C, Wedding U et al. Specific detection of Flt3 point mutations by highly sensitive real-time polymerase chain reaction in acute myeloid leukemia. J Lab Clin Med 2005; 145: 295–304.
Cilloni D, Saglio G . WT1 as a universal marker for minimal residual disease detection and quantification in myeloid leukemias and in myelodysplastic syndrome. Acta Haematol 2004; 112: 79–84.
Keilholz U, Menssen HD, Gaiger A, Menke A, Oji Y, Oka Y et al. Wilms’ tumour gene 1 (WT1) in human neoplasia. Leukemia 2005; 19: 1318–1323.
Ostergaard M, Olesen LH, Hasle H, Kjeldsen E, Hokland P . WT1 gene expression: an excellent tool for monitoring minimal residual disease in 70% of acute myeloid leukaemia patients—results from a single-centre study. Br J Haematol 2004; 125: 590–600.
Cilloni D, Renneville A, Hermitte F, Hills RK, Daly S, Jovanovic JV et al. 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 2009; 27: 5195–5201.
Weisser M, Kern W, Rauhut S, Schoch C, Hiddemann W, Haferlach T et al. Prognostic impact of RT-PCR-based quantification of WT1 gene expression during MRD monitoring of acute myeloid leukemia. Leukemia 2005; 19: 1416–1423.
Lapillonne H, Renneville A, Auvrignon A, Flamant C, Blaise A, Perot C et al. High WT1 expression after induction therapy predicts high risk of relapse and death in pediatric acute myeloid leukemia. J Clin Oncol 2006; 24: 1507–1515.
Cilloni D, Messa F, Arruga F, Defilippi I, Gottardi E, Fava M et al. Early prediction of treatment outcome in acute myeloid leukemia by measurement of WT1 transcript levels in peripheral blood samples collected after chemotherapy. Haematologica 2008; 93: 921–924.
Osborne D, Frost L, Tobal K, Liu Yin JA . Elevated levels of WT1 transcripts in bone marrow harvests are associated with a high relapse risk in patients autografted for acute myeloid leukaemia. Bone Marrow Transplant 2005; 36: 67–70.
Ogawa H, Ikegame K, Kawakami M, Tamaki H . WT1 gene transcript assay for relapse in acute leukemia after transplantation. Leuk Lymphoma 2004; 45: 1747–1753.
Ogawa H, Tamaki H, Ikegame K, Soma T, Kawakami M, Tsuboi A et al. The usefulness of monitoring WT1 gene transcripts for the prediction and management of relapse following allogeneic stem cell transplantation in acute type leukemia. Blood 2003; 101: 1698–1704.
Candoni A, Tiribelli M, Toffoletti E, Cilloni D, Chiarvesio A, Michelutti A et al. Quantitative assessment of WT1 gene expression after allogeneic stem cell transplantation is a useful tool for monitoring minimal residual disease in acute myeloid leukemia. Eur J Haematol 2009; 82: 61–68.
Niederwieser D, Maris M, Shizuru JA, Petersdorf E, Hegenbart U, Sandmaier BM et al. Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases. Blood 2003; 101: 1620–1629.
Bryant E, Martin PJ . Documentation of engraftment and characterization of chimerism following hematopoietic cell transplantation. In: Thomas ED, Blume KG, Forman SJ (eds). Hematopoietic Cell Transplantation, 2 edn. Boston, 1999, pp 197–206.
Bumm T, Muller C, Al-Ali HK, Krohn K, Shepherd P, Schmidt E et al. Emergence of clonal cytogenetic abnormalities in Ph− cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood 2003; 101: 1941–1949.
Lange T, Niederwieser DW, Deininger MW . Residual disease in chronic myeloid leukemia after induction of molecular remission. N Engl J Med 2003; 349: 1483–1484.
Ihaka R, Gentleman R . R a language for data analysis and graphics. J Comp Graph Stat 1996; 5: 299–314.
Bornhauser M, Oelschlaegel U, Platzbecker U, Bug G, Lutterbeck K, Kiehl MG et al. Monitoring of donor chimerism in sorted CD34+ peripheral blood cells allows the sensitive detection of imminent relapse after allogeneic stem cell transplantation. Haematologica 2009; 94: 1613–1617.
Bacher U, Kern W, Schoch C, Schnittger S, Hiddemann W, Haferlach T . 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 2006; 106: 839–847.
Mancini M, Cedrone M, Diverio D, Emanuel B, Stul M, Vranckx H et al. 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 2000; 14: 364–368.
Zeiser R, Spyridonidis A, Wasch R, Ihorst G, Grullich C, Bertz H et al. Evaluation of immunomodulatory treatment based on conventional and lineage-specific chimerism analysis in patients with myeloid malignancies after myeloablative allogeneic hematopoietic cell transplantation. Leukemia 2005; 19: 814–821.
Nyvold CG, Stentoft J, Braendstrup K, Melsvik D, Moestrup SK, Juhl-Christensen C et al. Wilms’ tumor 1 mutation accumulated during therapy in acute myeloid leukemia: Biological and clinical implications. Leukemia 2006; 20: 2051–2054.
Gaidzik VI, Schlenk RF, Moschny S, Becker A, Bullinger L, Corbacioglu A et al. Prognostic impact of WT1 mutations in cytogenetically normal acute myeloid leukemia (AML): A study of the German–Austrian AML Study Group (AMLSG). Blood 2009; 113: 4505–4511.
Bruggemann M, Raff T, Flohr T, Gokbuget N, Nakao M, Droese J et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood 2006; 107: 1116–1123.
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.
Bethge WA, Storer BE, Maris MB, Flowers ME, Maloney DG, Chauncey TR et al. Relapse or progression after hematopoietic cell transplantation using nonmyeloablative conditioning: effect of interventions on outcome. Exp Hematol 2003; 31: 974–980.
Metzelder S, Wang Y, Wollmer E, Wanzel M, Teichler S, Chaturvedi A et al. Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood 2009; 113: 6567–6571.
Cross M, Jaekel N, Krahl R, Junghanss C, Maschmeyer G, Tran T et al. Low levels of global (LINE) and CDH13 methylation at diagnosis and rapid clearance of marrow blasts correlate with a better haematological response to azacitidine in patients with newly diagnosed and refractory/relapsed AML not eligible for or resistant to chemotherapy: a multi-centre phase I/II-study of the East German Haematology and Oncology Study Group (OSHO). ASH Annual Meeting Abstracts 2009; 114: 2642.
Acknowledgements
We thank Janet Bogardt, Dagmar Crohn, Christa Döring, Christina Franke, Christine Günther, Evelyn Hennig, Ines Kovacs, Rainer Krahl, Christel Müller and Scarlet Musiol for their excellent assistance.
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Lange, T., Hubmann, M., Burkhardt, R. et al. 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, 498–505 (2011). https://doi.org/10.1038/leu.2010.283
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DOI: https://doi.org/10.1038/leu.2010.283
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