Best Practice & Research Clinical Haematology
Volume 23, Issue 1 , Pages 97-107 , March 2010

Is MRD eradication a desirable goal in CLL?

  • Carol Moreno, MD (Post-doctoral fellow)

      Affiliations

    • Haematology Department, Institute of Haematology and Oncology, Hospital Clínic, University of Barcelona, Spain
    • Corresponding Author InformationCorresponding author. Tel.: +34 93 227 54 75; Fax: +34 93 227 9811.
  • ,
  • Matthias Ritgen, MD (Post-doctoral fellow)

      Affiliations

    • Department of Medicine II, Haematology and Oncology Hospital Clinic, University of Schleswig-Holstein, Kiel, Germany
  • ,
  • Andy Rawstron, PhD (Consultant Clinical Scientist)

      Affiliations

    • Haematological Malignancy Diagnostic Service, St. James's Institute of Oncology, Bexley Wing, Beckett Street, Leeds, LS9 7TF, UK

References 

  1. Tam CS, O'Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112:975–980
  2. Bosch F, Abrisqueta P, Villamor N, et al. Rituximab, fludarabine, cyclophosphamide, and mitoxantrone: a new, highly active chemoimmunotherapy regimen for chronic lymphocytic leukemia. J Clin Oncol. 2009;27:4578–4584
  3. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111:5446–5456
  4. Cave H, van der Werff ten Bosch , Suciu S, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer–Childhood Leukemia Cooperative Group. N Engl J Med. 1998;339:591–598
  5. Lo CF, Diverio D, Pandolfi PP, et al. Molecular evaluation of residual disease as a predictor of relapse in acute promyelocytic leukaemia. Lancet. 1992;340:1437–1438
  6. Montserrat E. Treatment of chronic lymphocytic leukemia: achieving minimal residual disease-negative status as a goal. J Clin Oncol. 2005;23:2884–2885
  7. Moreton P, Kennedy B, Lucas G, et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol. 2005;23:2971–2979
  8. Bosch F, Ferrer A, Villamor N, et al. Fludarabine, cyclophosphamide, and mitoxantrone as initial therapy of chronic lymphocytic leukemia: high response rate and disease eradication. Clin Cancer Res. 2008;14:155–161
  9. Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996;87:4990–4997
  10. Provan D, Bartlett-Pandite L, Zwicky C, et al. Eradication of polymerase chain reaction-detectable chronic lymphocytic leukemia cells is associated with improved outcome after bone marrow transplantation. Blood. 1996;88:2228–2235
  11. van Dongen JJ, Langerak AW, Bruggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia. 2003;17:2257–2317
  12. Bruggemann M, Droese J, Bolz I, et al. Improved assessment of minimal residual disease in B cell malignancies using fluorogenic consensus probes for real-time quantitative PCR. Leukemia. 2000;14:1419–1425
  13. Pfitzner T, Reiser M, Barth S, et al. Quantitative molecular monitoring of residual tumor cells in chronic lymphocytic leukemia. Ann Hematol. 2002;81:258–266
  14. Moreno C, Villamor N, Colomer D, et al. Clinical significance of minimal residual disease, as assessed by different techniques, after stem cell transplantation for chronic lymphocytic leukemia. Blood. 2006;107:4563–4569
  15. Bottcher S, Ritgen M, Pott C, et al. Comparative analysis of minimal residual disease detection using four-color flow cytometry, consensus IgH-PCR, and quantitative IgH PCR in CLL after allogeneic and autologous stem cell transplantation. Leukemia. 2004;18:1637–1645
  16. Vuillier F, Claisse JF, Vandenvelde C, et al. Evaluation of residual disease in B-cell chronic lymphocytic leukemia patients in clinical and bone-marrow remission using CD5-CD19 markers and PCR study of gene rearrangements. Leuk Lymphoma. 1992;7:195–204
  17. Bomberger C, Singh-Jairam M, Rodey G, et al. Lymphoid reconstitution after autologous PBSC transplantation with FACS-sorted CD34+ hematopoietic progenitors. Blood. 1998;91:2588–2600
  18. Rawstron AC, Kennedy B, Evans PA, et al. Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy. Blood. 2001;98:29–35
  19. Rawstron AC, Villamor N, Ritgen M, et al. International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia. Leukemia. 2007;21:956–964
  20. Rawstron AC, de TR, Jack AS, Hillmen P. Flow cytometric protein expression profiling as a systematic approach for developing disease-specific assays: identification of a chronic lymphocytic leukaemia-specific assay for use in rituximab-containing regimens. Leukemia. 2006;20:2102–2110
  21. Bottcher S, Stilgenbauer S, Busch R, et al. Standardized MRD flow and ASO IGH RQ-PCR for MRD quantification in CLL patients after rituximab-containing immunochemotherapy: a comparative analysis. Leukemia. 2009;23:2007–2017
  22. Robak T, Blonski JZ, Kasznicki M, et al. Cladribine combined with cyclophosphamide is highly effective in the treatment of chronic lymphocytic leukemia. Hematol J. 2002;3:244–250
  23. Robertson LE, Huh YO, Butler JJ, et al. Response assessment in chronic lymphocytic leukemia after fludarabine plus prednisone: clinical, pathologic, immunophenotypic, and molecular analysis. Blood. 1992;80:29–36
  24. O'Brien SM, Kantarjian HM, Cortes J, et al. Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol. 2001;19:1414–1420
  25. Maloum K, Settegrana C, Chapiro E, et al. IGHV gene mutational status and LPL/ADAM29 gene expression as clinical outcome predictors in CLL patients in remission following treatment with oral fludarabine plus cyclophosphamide. Ann Hematol. 2009;88:1215–1221
  26. Bosch F, Ferrer A, Lopez-Guillermo A, et al. Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia. Br J Haematol. 2002;119:976–984
  27. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25:5616–5623
  28. Keating MJ, O'Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23:4079–4088
  29. Wierda W, O'Brien S, Wen S, et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol. 2005;23:4070–4078
  30. Hallek M, Fingerle-Rowson G, Fink AM, et al. Immunochemotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus fludarabine and cyclophosphamide (FC) improves response rates and progression-free survival (PFS) of previously untreated patients (pts) with advanced chronic lymphocytic leukemia (CLL). Blood. 2008;112:325
  31. Bottcher S, Fischer K, Stilgenbauer S, et al. Quantitative MRD assessments predict progression free survival in CLL patients treated with fludarabine and cyclophosphamide with or without rituximab – a prospective analysis in 471 patients from the randomized GCLLSG CLL8 trial. Blood. 2008;112:326
  32. Kwok M, Rawstron A, Varghese A, et al. Minimal residual disease is a predictor for progression-free and overall survival in chronic lymphocytic leukemia (CLL) that is independent of the type or line of therapy. Blood. 2009;114:226
  33. Castro JE, James DF, Sandoval-Sus JD, et al. Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia. Leukemia. 2009;23:1779–1789
  34. Faderl S, Wierda W, O'Brien S, et al. Fludarabine, cyclophosphamide, mitoxantrone plus rituximab (FCM-R) in frontline CLL <70 Years. Leuk Res. 2010;34:284–288
  35. Del PG, Del Principe MI, Buccisano F, et al. Consolidation and maintenance immunotherapy with rituximab improve clinical outcome in patients with B-cell chronic lymphocytic leukemia. Cancer. 2008;112:119–128
  36. O'Brien SM, Kantarjian HM, Thomas DA, et al. Alemtuzumab as treatment for residual disease after chemotherapy in patients with chronic lymphocytic leukemia. Cancer. 2003;98:2657–2663
  37. Montillo M, Tedeschi A, Miqueleiz S, et al. Alemtuzumab as consolidation after a response to fludarabine is effective in purging residual disease in patients with chronic lymphocytic leukemia. J Clin Oncol. 2006;24:2337–2342
  38. Schweighofer CD, Ritgen M, Eichhorst BF, et al. Consolidation with alemtuzumab improves progression-free survival in patients with chronic lymphocytic leukaemia (CLL) in first remission: long-term follow-up of a randomized phase III trial of the German CLL Study Group (GCLLSG). Br J Haematol. 2009;144:95–98
  39. Esteve J, Villamor N, Colomer D, Montserrat E. Different clinical value of minimal residual disease after autologous and allogenic stem cell transplantation for chronic lymphocytic leukemia. Blood. 2002;99:1873–1874
  40. Milligan DW, Fernandes S, Dasgupta R, et al. Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses. Blood. 2005;105:397–404
  41. Ritgen M, Stilgenbauer S, von NN, et al. Graft-versus-leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene status: implications of minimal residual disease measurement with quantitative PCR. Blood. 2004;104:2600–2602
  42. Dreger P, Brand R, Hansz J, et al. Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning. Leukemia. 2003;17:841–848
  43. Schetelig J, Thiede C, Bornhauser M, et al. Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol. 2003;21:2747–2753
  44. Sorror ML, Maris MB, Sandmaier BM, et al. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol. 2005;23:3819–3829
  45. Sorror ML, Storer BE, Sandmaier BM, et al. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol. 2008;26:4912–4920
  46. Esteve J, Montserrat E, Dreger P, et al. Stem cell transplantation (SCT) for chronic lymphocytic leukemia (CLL): outcome and prognostic factors after autologous and allogeneic transplants. Blood. 2001;98:482a
  47. Gribben JG, Zahrieh D, Stephans K, et al. Autologous and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia. Blood. 2005;106:4389–4396
  48. Doney KC, Chauncey T, Appelbaum FR. Allogeneic related donor hematopoietic stem cell transplantation for treatment of chronic lymphocytic leukemia. Bone Marrow Transplant. 2002;29:817–823
  49. Michallet M, Michallet AS, Le QH, et al. Conventional HLA-identical sibling bone marrow transplantation is able to cure chronic lymphocytic leukemia. A Study from the EBMT and IBMT Registries. Blood. 2003;102:474a
  50. Moreno C, Esteve J, Abrisqueta P, et al. Allogeneic stem-cell transplantation as a curative approach for chronic lymphocytic leukemia (CLL). The relevance of late relapses. The clinic of Barcelona experience and a succinct review of the literature. Annals of Oncology. 2008;19:384
  51. Ritgen M, Bottcher S, Stilgenbauer S, et al. Quantitative MRD monitoring identifies distinct GVL response patterns after allogeneic stem cell transplantation for chronic lymphocytic leukemia: results from the GCLLSG CLL3X trial. Leukemia. 2008;22:1377–1386
  52. Dreger P, Stilgenbauer S, Böttcher S, et al. Prognostic factors for outcome of nonmyeloablative allogeneic stem cell transplantation in poor-risk chronic lymphocytic leukemia (CLL): final results from a prospective multicenter trial (GCLLSG CLL3 Study). Blood. 2008;112:565
  53. Morrison VA, Rai KR, Peterson BL, et al. Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil: results of an intergroup study, cancer and leukemia group B 9011. J Clin Oncol. 2002;20:3878–3884
  54. Thornton PD, Bellas C, Santon A, et al. Richter's transformation of chronic lymphocytic leukemia. The possible role of fludarabine and the Epstein-Barr virus in its pathogenesis. Leuk Res. 2005;29:389–395
  55. Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007;370:230–239

PII: S1521-6926(10)00006-X

doi: 10.1016/j.beha.2010.01.005

Best Practice & Research Clinical Haematology
Volume 23, Issue 1 , Pages 97-107 , March 2010