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Successful peripheral blood stem cell mobilisation with filgrastim in patients with chronic myeloid leukaemia achieving complete cytogenetic response with imatinib, without increasing disease burden as measured by quantitative real-time PCR

Abstract

Imatinib mesylate (Glivec) is a selective inhibitor of bcr-abl tyrosine kinase, the product of the Philadelphia chromosome, which is the hallmark of chronic myeloid leukaemia (CML). With imatinib, complete cytogenetic response (CCR) can be achieved in over 70% of newly diagnosed patients with CML. However, the optimal long-term management of patients who achieve CCR after imatinib is unknown. With longer follow-up, it is anticipated that some patients are likely to progress and become candidates for autologous transplantation. We studied filgrastim (r-metHuG-CSF) mobilisation of peripheral blood stem cells (PBSC) in 32 patients who have achieved CCR with imatinib. Our data demonstrate that (1) the target CD34+ cell yields of 2.0 × 106/kg were attained with filgrastim 10 μg/kg/day, in 9/18 (50%) of patients during uninterrupted imatinib therapy, and in 10/14 (70%) when imatinib was temporarily withheld. The median CD34+ cell yield per aphaeresis was 0.70 × 106/kg (range 0.14–2.18) and 2.90 × 106/kg (range 0.15–8.71) in the two groups, respectively (P<0.005). (2) The cell yields did not correlate with the duration of imatinib administration. (3) There was no impact of the mobilisation procedure on the level of leukaemia as measured by serial blood bcr-abl levels using real-time quantitative PCR with either protocol. (4) bcr-abl remained detectable at low levels in the harvests in most but not all patients. In conclusion, filgrastim can safely be used to mobilise PBSC in patients who have achieved CCR with imatinib, but CD34+ cell yields are significantly improved when imatinib is temporarily withheld.

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References

  1. McGlave PB, De Fabritiis P, Deisseroth A, Goldman J, Barnett M, Reiffers J et al. Autologous transplants for chronic myeloid leukemia: results from eight transplant groups. Lancet 1994; 343: 1486–1488.

    Article  CAS  PubMed  Google Scholar 

  2. Bergamaschi G, Podesta M, Frassoni F, Rosti V, Carella AM, Saglio G et al. Restoration of normal polyclonal haemopoiesis in patients with chronic myeloid leukemia autografted with Ph-negative stem cells. Br J Haematol 1994; 87: 867–870.

    Article  CAS  PubMed  Google Scholar 

  3. Bhatia R, Verfaillie CM, Miller JS, McGlave PB . Autologous transplantation therapy for chronic myeloid leukaemia. Blood 1997; 89: 2623–2634.

    CAS  PubMed  Google Scholar 

  4. Carella AM, Celesti L, Lerma E, Dejana A, Frassoni F . Stem-cell mobilization for autografting in chronic myeloid leukemia. Blood Rev 1997; 11: 154–159.

    Article  CAS  PubMed  Google Scholar 

  5. Deisseroth AB, Zu Z, Claxton D, Hanania EG, Fu S, Ellerson D et al. Genetic marking shows that Ph+ cells present in autologous transplants of chronic myelogenous leukemia (CML) contribute to relapse after autologous bone marrow transplantation in CML. Blood 1994; 83: 3068–3076.

    CAS  PubMed  Google Scholar 

  6. Singer IO, Franklin IM . Autografting as first line treatment for chronic myeloid leukaemia. J Clin Pathol 1998; 51: 92–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996; 2: 561–566.

    Article  CAS  PubMed  Google Scholar 

  8. Savage DG, Antman KH . Imatinib mesylate – a new oral targeted therapy. N Engl J Med 2002; 346: 683–693.

    Article  CAS  PubMed  Google Scholar 

  9. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukaemia. N Engl J Med 2001; 344: 1038–1042.

    Article  CAS  PubMed  Google Scholar 

  10. Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002; 346: 645–652.

    Article  CAS  PubMed  Google Scholar 

  11. Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 2002; 99: 1928–1937.

    Article  CAS  PubMed  Google Scholar 

  12. Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OG et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 2002; 99: 3530–3539.

    Article  CAS  PubMed  Google Scholar 

  13. Branford S, Moore S, Grigg A, Szer J, Arthur C, Taylor K et al. Early measurement of BCR-ABL mRNA blood levels may be predictive of subsequent achievement of major cytogenetic response to Glivec in chronic myeloid leukemia. Blood 2001; 98: 613a.

    Google Scholar 

  14. Stentoft J, Pallisgaard N, Kjeldsen E, Holm MS, Nielsen JL, Hokland P . Kinetics of BCR-ABL fusion transcript levels in chronic myeloid leukaemia patients treated with STI571 measured by quantitative real-time polymerase chain reaction. Eur J Haematol 2001; 67:302–308.

    Article  CAS  PubMed  Google Scholar 

  15. Druker BJ for the IRIS Study Group. STI571 (Glivec imatinib) versus interferon (IFN) + cytarabine as initial therapy for patients with CML: results of a randomised study. Proc Am Soc Clin Oncol 2002; 21: 1a.

    Google Scholar 

  16. Goldman JM, Druker BJ . Chronic myeloid leukaemia: current treatment options. Blood 2001; 19: 2039–2042.

    Article  Google Scholar 

  17. Goldman J . Implications of imatinib mesylate for hematopoietic stem cell transplantation. Semin Hematol 2001; 38 (Suppl. 8): 28–34.

    Article  CAS  PubMed  Google Scholar 

  18. Apperley JF . Up-front transplantation for chronic myeloid leukaemia. 7th Congress of the European Hematology Association. The Hematol J 2002; Educational programme: 96–100.

  19. O'Brien SG, Rule SAJ . Position paper on imatinib mesylate in chronic myeloid leukaemia. Br J Haematol 2002; 119: 268–272.

    Article  PubMed  Google Scholar 

  20. Merx K, Müller MC, Kreil S, Lahaye T, Paschka P, Schoch C et al. Early reduction of BCR-ABL mRNA transcript levels predicts cytogenetic response in chronic phase CML patients treated with imatinib after failure of interferon α. Leukemia 2002; 16: 1579–1583.

    Article  CAS  PubMed  Google Scholar 

  21. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293: 876–880.

    Article  CAS  PubMed  Google Scholar 

  22. von Bubnoff N, Schneller F, Peschel C, Duyster J . Bcr-abl gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study. Lancet 2002; 359: 487.

    Article  CAS  PubMed  Google Scholar 

  23. Branford S, Rudzki Z, Walsh S, Grigg A, Arthur C, Taylor K et al. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood 2002; 99: 3472–3475.

    Article  CAS  PubMed  Google Scholar 

  24. Hochhaus A, Kreil S, Corbin AS, La Rosé P, Müller MC, Lahaye T et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 2002; 16: 2190–2196.

    Article  CAS  PubMed  Google Scholar 

  25. Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigier AJ . Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 2000; 96: 925–932.

    CAS  PubMed  Google Scholar 

  26. Lennard AL, Clark RE, Drummond MW, Rule S, Bolam S, Martin D on behalf of the MRC CML Working Party. Collection of peripheral blood stem cells in chronic myeloid leukaemia (CML) patients Philadelphia negative after treatment with imatinib mesylate (Glivec). Br J Haematol 2002; 117 (Suppl 1) 14.

    Google Scholar 

  27. Chang A, Ma DDF . The influence of flow cytometric gating strategy on the standardisation of CD34+ cell quantitation: an Australian multi-center study. Australasian BMT Scientists Study Group. J Hematother 1996; 5: 605–616.

    Article  CAS  PubMed  Google Scholar 

  28. Holland PM, Abrahamson RD, Watson R, Will S, Saiki RK, Gelfand DH . Detection of specific polymerase chain reaction products by utilizing the 5′ to 3′ exonuclease activity of Thermus aquaticus DNA polymerase. Proc Nat Acad Sci USA 1991; 88: 7276–7280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Branford S, Hughes TP, Rudzki Z . Monitoring chronic myeloid leukaemia therapy by real-time PCR in blood is a reliable alternative to bone marrow cytogenetics. Br J Haematol 1999; 107: 587–599.

    Article  CAS  PubMed  Google Scholar 

  30. Hughes TP, Grigg A, Szer J, Ho J, Ma D, Dale BM et al. Mobilization of predominantly Philadelphia chromosome-negative blood progenitors using cyclophosphamide and rHU-GCSG in early chronic-phase chronic myeloid leukaemia: correlation with Sokal prognostic index and haematological control. Br J Haematol 1997; 96: 635–640.

    Article  CAS  PubMed  Google Scholar 

  31. Deininger M, Pönisch W, Krahl R, Leiblein S, Edel E, Lange T et al. for the East German Study Group Haematology/Oncology. Chemotherapy for mobilisation of Ph-negative progenitor cells from patients with CML: impact of different mobilisation regimens. Bone Marrow Transplantation 2001; 27: 1125–1132.

    Article  CAS  PubMed  Google Scholar 

  32. Archimbaud E, Michallet M, Philip I, Charrin C, Clapisson G, Belhabri A et al. Granulocyte colony-stimulating factor given in addition to interferon-alpha to mobilize peripheral blood stem cells for autologous transplantation in chronic myeloid leukaemia. Br J Haematol 1997; 99: 678–684.

    Article  CAS  PubMed  Google Scholar 

  33. Holtz MS, Slovak ML, Zhang F, Sawyers CL, Forman SJ, Bhatia R . Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation. Blood 2002; 99: 3792–3800.

    Article  CAS  PubMed  Google Scholar 

  34. Morrison SJ, Wright DE, Weissman IL . Cyclophosphamide /granulocyte colony-stimulating factor induces hematopoietic stem cells to proliferate prior to mobilisation. Proc Nat Acad Sci USA 1997; 94: 1908–1913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Roberts MM, Swart BW, Simmons PJ, Basser RL, Begley CG, To LB . Prolonged release and c-kit expression of haemopoietic precursor cells mobilized by stem cell factor and granulocyte colony stimulating factor. Br J Haematol 1999; 104: 778–784.

    Article  CAS  PubMed  Google Scholar 

  36. Sawyers CL . Molecular studies in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Semin Hematol 2001; 38(S8): 15–21.

    Article  CAS  PubMed  Google Scholar 

  37. Hochhaus A, Lin F, Reiter A, Skladny H, van Rhee F, Shepherd PCA et al. Variable numbers of BCR-ABL transcripts persist in CML patients who achieved complete cytogenetic remission with interferon-α. Br J Haematol 1995; 91: 126–131.

    Article  CAS  PubMed  Google Scholar 

  38. Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002; 99: 319–325.

    Article  CAS  PubMed  Google Scholar 

  39. Hoepfl J, Miething C, Grundler R, Götze KS, Peschel C, Duyster J . Effects of imatinib on bone marrow engraftment in syngeneic mice. Leukemia 2002; 16: 1584–1588.

    Article  CAS  PubMed  Google Scholar 

  40. Fischer T, Reifenrath C, Hess GR, Corsetti MT, Kreil S, Beck J et al. Safety and efficacy of STI-571 (imatinib mesylate) in patients with bcr/abl-positive chronic myelogenous leukemia (CML) after autologous peripheral blood stem cell transplantation (PBSCT). Leukemia 2002; 16: 1220–1228.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank P Dyson and the transplant laboratory, and S Moore and the cytogenetics laboratory (Haematology, IMVS) for their specimen handling and cytogenetics analyses. We also thank H Tao, TH Loi and L Huckstepp (St Vincent's Hospital) for the sample preparation. The following clinicians have also contributed patients to our study: Drs M Wolf, C Arthur and AJ Concannon. This study was supported by grants from Novartis Australia, Amgen Australia and SVH Blood Diseases & Cancer Research Fund.

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Hui, C., Goh, K., White, D. et al. Successful peripheral blood stem cell mobilisation with filgrastim in patients with chronic myeloid leukaemia achieving complete cytogenetic response with imatinib, without increasing disease burden as measured by quantitative real-time PCR. Leukemia 17, 821–828 (2003). https://doi.org/10.1038/sj.leu.2402917

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