Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

Minimal Residual Disease in B-CLL

Minimal residual disease is common after allogeneic stem cell transplantation in patients with B cell chronic lymphocytic leukemia and may be controlled by graft-versus-host disease

Leukemia volume 14, pages 247–254 (2000)Cite this article

Abstract

Following allogeneic stem cell transplantation (SCT), we studied the presence of donor and recipient derived cells within the CD19+ B cell fraction, in patients with B cell chronic lymphocytic leukemia (CLL). The chimeric status of the six patients studied was further investigated with minimal residual disease (MRD) detection, by sequencing and using patient-specific primers derived from junctional regions of clonally rearranged immunoglobulin heavy-chain (IgH) receptor genes. To date, five of six patients are alive with a median follow-up time of 24 months (range 15–60) post-SCT. All patients experienced acute and chronic graft-versus-host disease and responded clinically to SCT. All patients were MRD positive after SCT, which correlated to mixed chimerism within the CD19+ cell fraction in all samples except one (25/26). High levels of tumor necrosis factor-α (TNF-α) and soluble interleukin-2 receptor (sIL-2R) indicated advanced disease, and patients with increased levels pre- and post-SCT were also those with the most long-lasting PCR-detectable MRD post-SCT. Hence, a high tumor burden pre-SCT may reflect the long duration of detectable MRD in patients with B-CLL after SCT. A durable anti-leukemic effect was probably important in these patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, Vaugier G, Potron G, Colona P, Oberling F, Thomas M, Tchernia G, Jacquillat C, Boivin P, Lesty C, Duault MT, Monconduit M, Belabbes S, Gremy F . A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis Cancer 1981 48: 198–206

    Article  CAS  PubMed  Google Scholar 

  2. Freedman AS, Boyd AW, Bieber FR, Daley J, Rosen K, Horowitz JC, Levy DN, Nadler LM . Normal cellular counterparts of B cell chronic lymphocytic leukemia Blood 1987 70: 418–427

    CAS  PubMed  Google Scholar 

  3. Hoffbrand AV, Panayiotidis P, Reittie J, Ganeshaguru K . Autocrine and paracrine growth loops in chronic lymphocytic leukemia Semin Hematol 1993 30: 306–317

    CAS  PubMed  Google Scholar 

  4. Lee JS, Dixon DO, Kantarjian HM, Keating MJ, Talpaz M . Prognosis of chronic lymphocytic leukemia: a multivariate regression analysis of 325 untreated patients Blood 1987 69: 929–936

    CAS  PubMed  Google Scholar 

  5. Montserrat E, Gomis F, Vallespi T, Rios A, Romero A, Soler J, Alcala A, Morey M, Ferran C, Diaz-Mediavilla J, Flores A, Woessner S, Batlle J, Gonzalez-Aza C, Rovira M, Reverter JC, Rozman C . Presenting features and prognosis of chronic lymphocytic leukemia in younger adults (see comments) Blood 1991 78: 1545–1551

    CAS  PubMed  Google Scholar 

  6. Michallet M, Archimbaud E, Bandini G, Rowlings PA, Deeg HJ, Gahrton G, Montserrat E, Rozman C, Gratwohl A, Gale RP . HLA-identical sibling bone marrow transplantation in younger patients with chronic lymphocytic leukemia. European Group for Blood and Marrow Transplantation and the International Bone Marrow Transplant Registry (see comments) Ann Intern Med 1996 124: 311–315

    Article  CAS  PubMed  Google Scholar 

  7. Khouri IF, Keating MJ, Vriesendorp HM, Reading CL, Przepiorka D, Huh YO, Andersson BS, van Besien KW, Mehra RC, Giralt SA, Ippoliti C, Marshall M, Thomas MW, O'Brien S, Robertson LE, Deisseroth AB, Champlin RE . Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: preliminary results J Clin Oncol 1994 12: 748–758

    Article  CAS  PubMed  Google Scholar 

  8. Provan D, Bartlett-Pandite L, Zwicky C, Neuberg D, Maddocks A, Corradini P, Soiffer R, Ritz J, Nadler LM, Gribben JG . Eradication of polymerase chain reaction-detectable chronic lymphocytic leukemia cells is associated with improved outcome after bone marrow transplantation Blood 1996 88: 2228–2235

    CAS  PubMed  Google Scholar 

  9. Maloum K, Pritsch O, Dighiero G . Minimal residual disease detection in B-cell malignancies by assessing IgH rearrangement Hematol Cell Ther 1997 39: 119–124

    Article  CAS  PubMed  Google Scholar 

  10. Esteve J, Villamor N, Colomer D, Bosch F, Lopez-Guillermo A, Rovira M, Urbano-Ispizua A, Sierra J, Carreras E, Montserrat E . Hematopoietic stem cell transplantation in chronic lymphocytic leukemia: a report of 12 patients from a single institution (see comments) Ann Oncol 1998 9: 167–172

    Article  CAS  PubMed  Google Scholar 

  11. Ugozzoli L, Yam P, Petz LD, Ferrara GB, Champlin RE, Forman SJ, Koyal D, Wallace RB . Amplification by the polymerase chain reaction of hypervariable regions of the human genome for evaluation of chimerism after bone marrow transplantation Blood 1991 77: 1607–1615

    CAS  PubMed  Google Scholar 

  12. Mackinnon S, Barnett L, Bourhis JH, Black P, Heller G, O'Reilly RJ . Myeloid and lymphoid chimerism after T-cell-depleted bone marrow transplantation: evaluation of conditioning regimens using the polymerase chain reaction to amplify human minisatellite regions of genomic DNA Blood 1992 80: 3235–3241

    CAS  PubMed  Google Scholar 

  13. Socie G, Lawler M, Gluckman E, McCann SR, Brison O . Studies on hemopoietic chimerism following allogeneic bone marrow transplantation in the molecular biology era Leukemia Res 1995 19: 497–504

    Article  CAS  Google Scholar 

  14. Semenzato G, Foa R, Agostini C, Zambello R, Trentin L, Vinante F, Benedetti F, Chilosi M, Pizzolo G . High serum levels of soluble interleukin 2 receptor in patients with B chronic lymphocytic leukemia Blood 1987 70: 396–400

    CAS  PubMed  Google Scholar 

  15. Adami F, Guarini A, Pini M, Siviero F, Sancetta R, Massaia M, Trentin L, Foa R, Semenzato G . Serum levels of tumour necrosis factor-alpha in patients with B-cell chronic lymphocytic leukaemia Eur J Cancer 1994 30A: 1259–1263

    Article  CAS  PubMed  Google Scholar 

  16. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, Rai KR . National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment Blood 1996 87: 4990–4997

    CAS  PubMed  Google Scholar 

  17. Ringden O, Remberger M, Persson U, Ljungman P, Aldener A, Andstrom E, Aschan J, Bolme P, Dahllof G, Dalianis T, Gahrton G, Hägglund H, Lönnqvist B, Ollerup O, Shanwell A, Sparrelid E, Winiarski J, Öberg M, Möller E . Similar incidence of graft-versus-host disease using HLA-A, -B and -DR identical unrelated bone marrow donors as with HLA-identical siblings Bone Marrow Transplant 1995 15: 619–625

    CAS  PubMed  Google Scholar 

  18. Storb R, Deeg HJ, Whitehead J, Appelbaum F, Beatty P, Bensinger W, Buckner CD, Clift R, Doney K, Farewell V, Hansen J, Hill R, Lum L, Martin P, McGuffin R, Sanders J, Stewart P, Sullivan K, Witherspoon R, Yee G, Thomas ED . Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia New Engl J Med 1986 314: 729–735

    Article  CAS  PubMed  Google Scholar 

  19. Ringden O, Pihlstedt P, Markling L, Aschan J, Baryd I, Ljungman P, Lonnqvist B, Tollemar J, Janossy G, Sundberg B . Prevention of graft-versus-host disease with T cell depletion or cyclosporin and methotrexate. A randomized trial in adult leukemic marrow recipients Bone Marrow Transplant 1991 7: 221–226

    CAS  PubMed  Google Scholar 

  20. Budowle B, Chakraborty R, Giusti AM, Eisenberg AJ, Allen RC . Analysis of the VNTR locus D1S80 by the PCR followed by high-resolution PAGE Am J Hum Genet 1991 48: 137–144

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Horn GT, Richards B, Klinger KW . Amplification of a highly polymorphic VNTR segment by the polymerase chain reaction Nucleic Acids Res 1989 17: 2140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Eubanks JH, Selleri L, Hart R, Rosette C, Evans GA . Isolation, localization, and physical mapping of a highly polymorphic locus on human chromosome 11q13 Genomics 1991 11: 720–729

    Article  CAS  PubMed  Google Scholar 

  23. Decorte R, Cuppens H, Marynen P, Cassiman JJ . Rapid detection of hypervariable regions by the polymerase chain reaction technique DNA Cell Biol 1990 9: 461–469

    Article  CAS  PubMed  Google Scholar 

  24. Buchmayer H, Rumpold H, Mannhalter C . Identification of a variable number tandem repeat region in the human T cell receptor alpha-delta (TCRAD) locus Hum Genet 1996 98: 333–335

    Article  CAS  PubMed  Google Scholar 

  25. Jeffreys AJ, Wilson V, Neumann R, Keyte J . Amplification of human minisatellites by the polymerase chain reaction: towards DNA fingerprinting of single cells Nucleic Acids Res 1988 16: 10953–10971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yamada M, Hudson S, Tournay O, Bittenbender S, Shane SS, Lange B, Tsujimoto Y, Caton AJ, Rovera G . Detection of minimal disease in hematopoietic malignancies of the B-cell lineage by using third-complementarity-determining region (CDR-III)-specific probes Proc Natl Acad Sci USA 1989 86: 5123–5127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Steward CG, Goulden NJ, Potter MN, Oakhill A . The use of the polymerase chain reaction to detect minimal residual disease in childhood acute lymphoblastic leukaemia Eur J Cancer 1993 29A: 1192–1198

    CAS  PubMed  Google Scholar 

  28. Flinn IW, Vogelsang G . Bone marrow transplantation for chronic lymphocytic leukemia Semin Oncol 1998 25: 60–64

    CAS  PubMed  Google Scholar 

  29. Rabinowe SN, Soiffer RJ, Gribben JG, Daley H, Freedman AS, Daley J, Pesek K, Neuberg D, Pinkus G, Leavitt PR, Spector NA, Grossbard ML, Anderson K, Robertson MJ, Mauch P, Chayt-Marcus K, Ritz J, Nadler LM . Autologous and allogeneic bone marrow transplantation for poor prognosis patients with B-cell chronic lymphocytic leukemia Blood 1993 82: 1366–1376

    CAS  PubMed  Google Scholar 

  30. Rondon G, Giralt S, Huh Y, Khouri I, Andersson B, Andreeff M, Champlin R . Graft-versus-leukemia effect after allogeneic bone marrow transplantation for chronic lymphocytic leukemia Bone Marrow Transplant 1996 18: 669–672

    CAS  PubMed  Google Scholar 

  31. Jarque I, Palau J, Sanz GF, Guinot M, Gomis F, Martin G, Martinez J, Sanz MA . Delayed complete response after allogeneic bone marrow transplantation in chronic lymphocytic leukemia (letter) Blood 1993 82: 1036–1038

    CAS  PubMed  Google Scholar 

  32. Weiden PL, Sullivan KM, Flournoy N, Storb R, Thomas ED . Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation New Engl J Med 1981 304: 1529–1533

    Article  CAS  PubMed  Google Scholar 

  33. Wright SJ, Keating MJ . Cyclosporine A in chronic lymphocytic leukemia: dual anti-leukemic and immunosuppressive role? Leuk Lymphoma 1995 20: 131–136

    Article  CAS  PubMed  Google Scholar 

  34. Khouri IF, Keating M, Korbling M, Przepiorka D, Anderlini P, O'Brien S, Giralt S, Ippoliti C, von Wolff B, Gajewski J, Donato M, Claxton D, Ueno N, Andersson B, Gee A, Champlin R . Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies J Clin Oncol 1998 16: 2817–2824

    Article  CAS  PubMed  Google Scholar 

  35. Mehta J, Powles R, Kulkarni S, Treleaven J, Singhal S . Induction of graft-versus-host disease as immunotherapy of leukemia relapsing after allogeneic transplantation: single-center experience of 32 adult patients Bone Marrow Transplant 1997 20: 129–135

    Article  CAS  PubMed  Google Scholar 

  36. Martino R, Brunet S, Garcia A, Sureda A, Soler J, Martinez C, Domingo-Albos A, Baiget M . Various patterns of chimerism after allogeneic bone marrow transplantation for advanced chronic lymphocytic leukemia Bone Marrow Transplant 1995 16: 783–786

    CAS  PubMed  Google Scholar 

  37. Gribben JG, Neuberg D, Barber M, Moore J, Pesek KW, Freedman AS, Nadler LM . Detection of residual lymphoma cells by polymerase chain reaction in peripheral blood is significantly less predictive for relapse than detection in bone marrow Blood 1994 83: 3800–3807

    CAS  PubMed  Google Scholar 

  38. Lin F, Goldman JM, Cross NC . A comparison of the sensitivity of blood and bone marrow for the detection of minimal residual disease in chronic myeloid leukemia (see comments) Br J Haematol 1994 86: 683–685

    Article  CAS  PubMed  Google Scholar 

  39. Barak V, Ginzburg M, Kalickman I, Polliack A . Serum soluble interleukin-2 receptor levels are associated with clinical disease status and histopathological grade in non-Hodgkin's lymphoma and chronic lymphocytic leukemia Leuk Lymphoma 1992 7: 431–438

    Article  CAS  PubMed  Google Scholar 

  40. Cordingley FT, Bianchi A, Hoffbrand AV, Reittie JE, Heslop HE, Vyakarnam A, Turner M, Meager A, Brenner MK . Tumour necrosis factor as an autocrine tumour growth factor for chronic B-cell malignancies Lancet 1988 1: 969–971

    Article  CAS  PubMed  Google Scholar 

  41. van Kooten C, Rensink I, Aarden L, van Oers R . Interleukin-4 inhibits both paracrine and autocrine tumor necrosis factor-alpha-induced proliferation of B chronic lymphocytic leukemia cells Blood 1992 80: 1299–1306

    CAS  PubMed  Google Scholar 

  42. van Kooten C, Rensink I, Aarden L, van Oers R . Cytokines and intracellular signals involved in the regulation of B-CLL proliferation Leuk Lymphoma 1993 12: 27–33

    Article  CAS  PubMed  Google Scholar 

  43. Bartik MM, Welker D, Kay NE . Impairments in immune cell function in B cell chronic lymphocytic leukemia Semin Oncol 1998 25: 27–33

    CAS  PubMed  Google Scholar 

  44. Miyashita T, Reed JC . Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line Blood 1993 81: 151–157

    CAS  PubMed  Google Scholar 

  45. Sentman CL, Shutter JR, Hockenbery D, Kanagawa O, Korsmeyer SJ . bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes Cell 1991 67: 879–888

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the nursing stuff at the Center for Allogeneic stem cell transplantation and Depts of Hematology and Pediatrics, for excellent patient care. We also thank Lotta Tammik and Giti Bayat for excellent technical assistance and Sussanne Öhman for collecting blood samples. This study was supported by grants from the Swedish Cancer Foundation (0070-B96-10XAC), the Children's Cancer Foundation (1994-060) and the Swedish Medical Research Council (K97-06X-05971-17A).

Author information

Authors and Affiliations

  1. Centre for Allogeneic Stemcell Transplantation, Karolinska Institute at Huddinge Hospital, Huddinge, Sweden

    J Mattsson, M Uzunel, M Remberger & O Ringdén

  2. Department of Clinical Immunology, Karolinska Institute at Huddinge Hospital, Huddinge, Sweden

    J Mattsson, M Uzunel, M Remberger & O Ringdén

  3. Department of Hematology, Karolinska Institute at Huddinge Hospital, Huddinge, Sweden

    P Ljungman & E Kimby

  4. Department of Surgery, Karolinska Institute at Huddinge Hospital, Huddinge, Sweden

    H Zetterquist

Authors
  1. J Mattsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Uzunel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Remberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P Ljungman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E Kimby
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. O Ringdén
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H Zetterquist
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mattsson, J., Uzunel, M., Remberger, M. et al. Minimal residual disease is common after allogeneic stem cell transplantation in patients with B cell chronic lymphocytic leukemia and may be controlled by graft-versus-host disease. Leukemia 14, 247–254 (2000). https://doi.org/10.1038/sj.leu.2401669

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2401669

Keywords

This article is cited by

Search

Advanced search

Quick links