Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1998 Jun;77(12):2291–2297. doi: 10.1038/bjc.1998.381

Early stem cell transplantation for chronic lymphocytic leukaemia: a chance for cure?

P Dreger 1, N von Neuhoff 1, R Kuse 1, R Sonnen 1, B Glass 1, L Uharek 1, R Schoch 1, H Löffler 1, N Schmitz 1
PMCID: PMC2150407  PMID: 9649148

Abstract

B-cell chronic lymphocytic leukaemia (CLL) cannot be cured by conventional therapy. To improve the prognosis of patients with CLL, we have designed a sequential treatment strategy that comprises intensive chemotherapy for mobilization of peripheral blood progenitor cells (PBPCs) and induction of minimal disease, followed by high-dose radiochemotherapy with stem cell reinfusion and post-transplant molecular monitoring by polymerase chain reaction (PCR) amplification of the complementary determining region III (CDRIII) gene. In a prospective study, we have evaluated this protocol in 18 patients with CLL, also including early stages of the disease. The median age was 49 (29-61) years; Binet stages were A, six; B, nine; and C, three. Adverse prognostic factors [high lymphocyte count and/or diffuse bone marrow (BM) infiltration] were present in 16 out of 18 patients. All patients showed a clone-specific molecular marker as demonstrated by PCR amplification of CDRIII rearrangements. For stem cell mobilization and reduction of tumour load, one to two cycles of Dexa-BEAM chemotherapy were administered, resulting in minimal disease (circulating lymphoma cells <1 x 10(9) l(-1); BM infiltration <20%; lymphomas <2 cm) in 16 out of 18 patients, including four patients who already had minimal disease before Dexa-BEAM. Stem cell harvesting was successful in 14 patients. All grafts [three BM, 11 peripheral blood (PB)] were purged from leukaemic cells using immunomagnetic methods. Thirteen patients having achieved minimal disease were reinfused with purged autologous stem cells (ASC) after preparation with total body irradiation and cyclophosphamide. Engraftment was delayed in patients receiving BM (n = 3) but prompt [neutrophils >0.5 x 10(9) l(-1) after 10 (9-13) days, platelets >20 x 10(9) l(-1) after 11 (9-214) days] in patients restored with PBPCs (n = 10). Procedure-related deaths did not occur. Although the results of CDRIII PCR suggest persistence or recurrence of the leukaemic clone in at least three cases, to date only one patient has relapsed, whereas all others survive without clinical evidence of disease with a maximum follow-up of 48 months. We conclude that sequential high-dose therapy using Dexa-BEAM and autologous stem cell transplantation is a safe and highly effective treatment for patients with CLL. However, a longer follow-up is needed to assess whether definite cures can be achieved using this strategy.

Full text

PDF
2295

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bastion Y., Brice P., Haioun C., Sonet A., Salles G., Marolleau J. P., Espinouse D., Reyes F., Gisselbrecht C., Coiffier B. Intensive therapy with peripheral blood progenitor cell transplantation in 60 patients with poor-prognosis follicular lymphoma. Blood. 1995 Oct 15;86(8):3257–3262. [PubMed] [Google Scholar]
  2. Brugger W., Henschler R., Heimfeld S., Berenson R. J., Mertelsmann R., Kanz L. Positively selected autologous blood CD34+ cells and unseparated peripheral blood progenitor cells mediate identical hematopoietic engraftment after high-dose VP16, ifosfamide, carboplatin, and epirubicin. Blood. 1994 Sep 1;84(5):1421–1426. [PubMed] [Google Scholar]
  3. Dreger P., Klöss M., Petersen B., Haferlach T., Löffler H., Loeffler M., Schmitz N. Autologous progenitor cell transplantation: prior exposure to stem cell-toxic drugs determines yield and engraftment of peripheral blood progenitor cell but not of bone marrow grafts. Blood. 1995 Nov 15;86(10):3970–3978. [PubMed] [Google Scholar]
  4. Dreger P., Marquardt P., Haferlach T., Jacobs S., Mülverstedt T., Eckstein V., Suttorp M., Löffler H., Müller-Ruchholtz W., Schmitz N. Effective mobilisation of peripheral blood progenitor cells with 'Dexa-BEAM' and G-CSF: timing of harvesting and composition of the leukapheresis product. Br J Cancer. 1993 Nov;68(5):950–957. doi: 10.1038/bjc.1993.460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dreger P., Schmitz N. The role of stem cell transplantation in the treatment of chronic lymphocytic leukemia. Leukemia. 1997 Apr;11 (Suppl 2):S42–S45. [PubMed] [Google Scholar]
  6. Döhner H., Fischer K., Bentz M., Hansen K., Benner A., Cabot G., Diehl D., Schlenk R., Coy J., Stilgenbauer S. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood. 1995 Mar 15;85(6):1580–1589. [PubMed] [Google Scholar]
  7. Döhner H., Stilgenbauer S., James M. R., Benner A., Weilguni T., Bentz M., Fischer K., Hunstein W., Lichter P. 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis. Blood. 1997 Apr 1;89(7):2516–2522. [PubMed] [Google Scholar]
  8. Fischer A. M., Simon F., Le Deist F., Blanche S., Griscelli C., Fischer A. Prospective study of the occurrence of monoclonal gammapathies following bone marrow transplantation in young children. Transplantation. 1990 Apr;49(4):731–735. doi: 10.1097/00007890-199004000-00015. [DOI] [PubMed] [Google Scholar]
  9. Haas R., Moos M., Möhle R., Döhner H., Witt B., Goldschmidt H., Murea S., Flentje M., Wannenmacher M., Hunstein W. High-dose therapy with peripheral blood progenitor cell transplantation in low-grade non-Hodgkin's lymphoma. Bone Marrow Transplant. 1996 Feb;17(2):149–155. [PubMed] [Google Scholar]
  10. Hallek M., Wanders L., Ostwald M., Busch R., Senekowitsch R., Stern S., Schick H. D., Kuhn-Hallek I., Emmerich B. Serum beta(2)-microglobulin and serum thymidine kinase are independent predictors of progression-free survival in chronic lymphocytic leukemia and immunocytoma. Leuk Lymphoma. 1996 Aug;22(5-6):439–447. doi: 10.3109/10428199609054782. [DOI] [PubMed] [Google Scholar]
  11. Harris N. L., Jaffe E. S., Stein H., Banks P. M., Chan J. K., Cleary M. L., Delsol G., De Wolf-Peeters C., Falini B., Gatter K. C. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994 Sep 1;84(5):1361–1392. [PubMed] [Google Scholar]
  12. Itälä M., Pelliniemi T. T., Rajamäki A., Remes K. Autologous blood cell transplantation in B-CLL: response to chemotherapy prior to mobilization predicts the stem cell yield. Bone Marrow Transplant. 1997 Apr;19(7):647–651. doi: 10.1038/sj.bmt.1700730. [DOI] [PubMed] [Google Scholar]
  13. Keating M. J., O'Brien S., Kantarjian H., Plunkett W., Estey E., Koller C., Beran M., Freireich E. J. Long-term follow-up of patients with chronic lymphocytic leukemia treated with fludarabine as a single agent. Blood. 1993 Jun 1;81(11):2878–2884. [PubMed] [Google Scholar]
  14. Khouri I. F., Keating M. J., Vriesendorp H. M., Reading C. L., Przepiorka D., Huh Y. O., Andersson B. S., van Besien K. W., Mehra R. C., Giralt S. A. Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: preliminary results. J Clin Oncol. 1994 Apr;12(4):748–758. doi: 10.1200/JCO.1994.12.4.748. [DOI] [PubMed] [Google Scholar]
  15. Linke B., Pyttlich J., Tiemann M., Suttorp M., Parwaresch R., Hiddemann W., Kneba M. Identification and structural analysis of rearranged immunoglobulin heavy chain genes in lymphomas and leukemias. Leukemia. 1995 May;9(5):840–847. [PubMed] [Google Scholar]
  16. Michallet M., Archimbaud E., Bandini G., Rowlings P. A., Deeg H. J., Gahrton G., Montserrat E., Rozman C., Gratwohl A., Gale R. P. 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. Ann Intern Med. 1996 Feb 1;124(3):311–315. doi: 10.7326/0003-4819-124-3-199602010-00005. [DOI] [PubMed] [Google Scholar]
  17. Mitus A. J., Stein R., Rappeport J. M., Antin J. H., Weinstein H. J., Alper C. A., Smith B. R. Monoclonal and oligoclonal gammopathy after bone marrow transplantation. Blood. 1989 Dec;74(8):2764–2768. [PubMed] [Google Scholar]
  18. Paulus U., Schmitz N., Viehmann K., von Neuhoff N., Dreger P. Combined positive/negative selection for highly effective purging of PBPC grafts: towards clinical application in patients with B-CLL. Bone Marrow Transplant. 1997 Sep;20(5):415–420. doi: 10.1038/sj.bmt.1700914. [DOI] [PubMed] [Google Scholar]
  19. Pfreundschuh M. G., Rueffer U., Lathan B., Schmitz N., Brosteanu O., Hasenclever D., Haas R., Kirchner H., Koch P., Kuse R. Dexa-BEAM in patients with Hodgkin's disease refractory to multidrug chemotherapy regimens: a trial of the German Hodgkin's Disease Study Group. J Clin Oncol. 1994 Mar;12(3):580–586. doi: 10.1200/JCO.1994.12.3.580. [DOI] [PubMed] [Google Scholar]
  20. Provan D., Bartlett-Pandite L., Zwicky C., Neuberg D., Maddocks A., Corradini P., Soiffer R., Ritz J., Nadler L. M., Gribben J. G. Eradication of polymerase chain reaction-detectable chronic lymphocytic leukemia cells is associated with improved outcome after bone marrow transplantation. Blood. 1996 Sep 15;88(6):2228–2235. [PubMed] [Google Scholar]
  21. Rabinowe S. N., Soiffer R. J., Gribben J. G., Daley H., Freedman A. S., Daley J., Pesek K., Neuberg D., Pinkus G., Leavitt P. R. Autologous and allogeneic bone marrow transplantation for poor prognosis patients with B-cell chronic lymphocytic leukemia. Blood. 1993 Aug 15;82(4):1366–1376. [PubMed] [Google Scholar]
  22. Rozman C., Montserrat E. Chronic lymphocytic leukemia. N Engl J Med. 1995 Oct 19;333(16):1052–1057. doi: 10.1056/NEJM199510193331606. [DOI] [PubMed] [Google Scholar]
  23. Schmitz N., Linch D. C., Dreger P., Goldstone A. H., Boogaerts M. A., Ferrant A., Demuynck H. M., Link H., Zander A., Barge A. Randomised trial of filgrastim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients. Lancet. 1996 Feb 10;347(8998):353–357. doi: 10.1016/s0140-6736(96)90536-x. [DOI] [PubMed] [Google Scholar]
  24. Schroeder H. W., Jr, Dighiero G. The pathogenesis of chronic lymphocytic leukemia: analysis of the antibody repertoire. Immunol Today. 1994 Jun;15(6):288–294. doi: 10.1016/0167-5699(94)90009-4. [DOI] [PubMed] [Google Scholar]
  25. Shpall E. J., Jones R. B., Bearman S. I., Franklin W. A., Archer P. G., Curiel T., Bitter M., Claman H. N., Stemmer S. M., Purdy M. Transplantation of enriched CD34-positive autologous marrow into breast cancer patients following high-dose chemotherapy: influence of CD34-positive peripheral-blood progenitors and growth factors on engraftment. J Clin Oncol. 1994 Jan;12(1):28–36. doi: 10.1200/JCO.1994.12.1.28. [DOI] [PubMed] [Google Scholar]
  26. Sorensen J. M., Vena D. A., Fallavollita A., Chun H. G., Cheson B. D. Treatment of refractory chronic lymphocytic leukemia with fludarabine phosphate via the group C protocol mechanism of the National Cancer Institute: five-year follow-up report. J Clin Oncol. 1997 Feb;15(2):458–465. doi: 10.1200/JCO.1997.15.2.458. [DOI] [PubMed] [Google Scholar]
  27. Stansfeld A. G., Diebold J., Noel H., Kapanci Y., Rilke F., Kelényi G., Sundstrom C., Lennert K., van Unnik J. A., Mioduszewska O. Updated Kiel classification for lymphomas. Lancet. 1988 Feb 6;1(8580):292–293. doi: 10.1016/s0140-6736(88)90367-4. [DOI] [PubMed] [Google Scholar]
  28. Straka C., Drexler E., Mitterer M., Langenmayer I., Pfefferkorn L., Stade B., Koll R., Emmerich B. Autotransplantation of B-cell purged peripheral blood progenitor cells in B-cell lymphoma. Lancet. 1995 Mar 25;345(8952):797–798. doi: 10.1016/s0140-6736(95)90678-9. [DOI] [PubMed] [Google Scholar]
  29. Suttorp M., von Neuhoff N., Tiemann M., Dreger P., Schaub J., Löffer H., Parwaresch R., Schmitz N. Precast commercial polyacrylamide gels for separation of DNA amplificates by temperature gradient gel electrophoresis: application to clonality analysis of lymphomas. Electrophoresis. 1996 Apr;17(4):672–677. doi: 10.1002/elps.1150170408. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES