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Acute Lymphoblastic Leukaemia

Autologous bone marrow transplantation for childhood acute lymphoblastic leukemia: a novel combined approach consisting of ex vivo marrow purging, modulation of multi-drug resistance, induction of autograft vs leukemia effect, and post-transplant immuno- and chemotherapy (PTIC)

Abstract

In an attempt to reduce the high relapse rate associated with ABMT, five children with high-risk first CR and 19 in second or subsequent CR lacking matched family allogeneic donors underwent ABMT with chemopurged bone marrow utilizing verapamil (VPL), vincristine, and VP-16. Patients were conditioned with TBI, VPL bolus and infusion with VP-16 and cyclophosphamide. The first cohort of patients (n = 4) received only cyclosporin A (CsA). The second cohort (n = 7) received CsA and alpha interferon (total = 11 with post-transplant immunotherapy alone.) The third cohort (n = 13) received CsA and six alternating cycles of αIFN and chemotherapy and six additional cycles of chemotherapy (vincristine, VP-16, Ara-C, prednisone) followed by G-CSF (post-transplant immune chemotherapy (PTIC)). The 2-year DFS is 42 ± 10% (90% confidence interval (CI) is 26.5–58.5%) and 2-year overall survival is 54 ± 10% (90% CI is 37.5–70.5%). Furthermore, patients receiving PTIC (n = 13) vsimmunotherapy alone (CsA ± αIFN) (n = 11) had a substantially better 2 year DFS and OS: 69 ± 13% vs 13 ± 12% and 85 ± 10% vs 25 ± 15% (P = 0.008 and P = 0.06, respectively). These results suggest that the use of ABMT with chemopurging, combined with PTIC is well tolerated and may be an alternative new approach in the treatment of a subset of children with high-risk first CR or second CR ALL who lack closely matched family-related allogeneic donors. Bone Marrow Transplantation (2001) 27, 145–153.

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References

  1. Pui CH, Evans WE . Acute lymphoblastic leukemia New Engl J Med 1998 339: 605–615

    Article  CAS  PubMed  Google Scholar 

  2. Henze G, Fengler R, Hartmann R et al. Six-year experience with a comprehensive approach to the treatment of recurrent childhood acute lymphoblastic leukemia (ALL-REZ BFM 85). A relapse study of the BFM group Blood 1991 78: 1166–1172

    CAS  PubMed  Google Scholar 

  3. Parsons SK, Castellino SM, Lehmann LE et al. Relapsed acute lymphoblastic leukemia: similar outcomes for autologous and allogeneic marrow transplantation in selected children Bone Marrow Transplant 1996 17: 763–768

    CAS  PubMed  Google Scholar 

  4. Barrett AJ, Horowitz MM, Pollock BH et al. Bone marrow transplants from HLA-identical siblings as compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission (see comments) New Engl J Med 1994 331: 1253–1258

    Article  CAS  PubMed  Google Scholar 

  5. Billett AL, Kornmehl E, Tarbell NJ et al. Autologous bone marrow transplantation after a long first remission for children with recurrent acute lymphoblastic leukemia Blood 1993 81: 1651–1657

    CAS  PubMed  Google Scholar 

  6. Weisdorf DJ, Billett AL, Hannan P . Autologous versus unrelated donor allogeneic marrow transplantation for acute lymphoblastic leukemia Blood 1997 90: 2962–2968

    CAS  PubMed  Google Scholar 

  7. Yotnda P, Mintz P, Grigoriadou K et al. Analysis of T-cell defects in the specific immune response against acute lymphoblastic leukemia cells Exp Hematol 1999 27: 1375–1383

    Article  CAS  PubMed  Google Scholar 

  8. Tsuruo T, Iida H, Naganuma K et al. Promotion by verapamil of vincristine responsiveness in tumor cell lines inherently resistant to the drug Cancer Res 1983 43: 808–813

    CAS  PubMed  Google Scholar 

  9. Yalowich JC, Ross WE . Verapamil-induced augmentation of etoposide accumulation in L1210 cells in vitro Cancer Res 1985 45: 1651–1656

    CAS  PubMed  Google Scholar 

  10. Cairo MS, Siegel S, Anas N, Sender L . Clinical trial of continuous infusion verapamil, bolus vinblastine, and continuous infusion VP-16 in drug-resistant pediatric tumors Cancer Res 1989 49: 1063–1066

    CAS  PubMed  Google Scholar 

  11. Cairo MS, Toy C, Sender L et al. Combination chemotherapy and verapamil to purge drug resistant leukemia cells from human bone marrow. In: Gross S, Gee AP, Worthington-White DA (eds) Prog Clin Biol Res Wiley Liss: New York 1990 47–55

    Google Scholar 

  12. Cairo M, Plunkett J, Gillan E et al. A novel preparative and purging regimen employing verapamil to modulate multiple drug resistance during autologous bone marrow transplant in acute lymphoblastic leukemia: a pilot study AACR Proc 1992 33: 233 (Abstr.)

    Google Scholar 

  13. Chang TT, Gulati SC, Chou TC et al. Synergistic effect of 4-hydroperoxycyclophosphamide and etoposide on a human promyelocytic leukemia cell line (HL-60) demonstrated by computer analysis Cancer Res 1985 45: 2434–2439

    CAS  PubMed  Google Scholar 

  14. Dombernowsky P, Nissen NI . Combination chemotherapy with 4′Demethylepipodophyllotoxin 9-(4,6–0- ethylidene-beta-D-glucopyranoside), VP 16–213 (NSC 141540) in L1210 leukemia Eur J Cancer 1976 12: 181–188

    Article  CAS  PubMed  Google Scholar 

  15. Tiley C, Powles R, Treleaven J et al. Feasibility and efficacy of maintenance chemotherapy following autologous bone marrow transplantation for first remission acute lymphoblastic leukaemia Bone Marrow Transplant 1993 12: 449–455

    CAS  PubMed  Google Scholar 

  16. Gruhn B, Hafer R, Kosmehl H et al. Cyclosporin A-induced graft-versus-host disease following autologous bone marrow and stem cell transplantation in hematological malignancies of childhood Bone Marrow Transplant 1998 21: 901–907

    Article  CAS  PubMed  Google Scholar 

  17. Ratanatharathorn V, Uberti J, Karanes C et al. Phase I study of alpha-interferon augmentation of cyclosporine-induced graft versus host disease in recipients of autologous bone marrow transplantation Bone Marrow Transplant 1994 13: 625–630

    CAS  PubMed  Google Scholar 

  18. Kaplan E, Meier P . Nonparametric estimation from incomplete observations J Am Stat Assoc 1958 53: 457

    Article  Google Scholar 

  19. Collet D . Modeling Survival Data in Medical Research Chapman and Hall: London 1994

    Book  Google Scholar 

  20. Maldonado MS, Diaz-Heredia C, Badell I et al. Autologous bone marrow transplantation with monoclonal antibody purged marrow for children with acute lymphoblastic leukemia in second remission. Spanish Working Party for BMT in Children Bone Marrow Transplant 1998 22: 1043–1047

    Article  CAS  PubMed  Google Scholar 

  21. Canals C, Torrico C, Picon M et al. Immunomagnetic bone marrow purging in children with acute lymphoblastic leukemia J Hematother 1997 6: 261–268

    Article  CAS  PubMed  Google Scholar 

  22. Douay L, Mary JY, Giarratana MC et al. Establishment of a reliable experimental procedure for bone marrow purging with mafosfamide (ASTA Z 7557) Exp Hematol 1989 17: 429–432

    CAS  PubMed  Google Scholar 

  23. Kaizer H, Stuart RK, Brookmeyer R et al. Autologous bone marrow transplantation in acute leukemia: a phase I study of in vitro treatment of marrow with 4-hydroperoxycyclophosphamide to purge tumor cells Blood 1985 65: 1504–1510

    CAS  PubMed  Google Scholar 

  24. Gorin NC, Aegerter P, Auvert B . Autologous bone marrow transplantation for acute leukemia in remission: an analysis of 1322 cases Hamatol Bluttransfus 1990 33: 660–666

    CAS  Google Scholar 

  25. Gribben JG, Freedman AS, Neuberg D et al. Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma (see comments) New Engl J Med 1991 325: 1525–1533

    Article  CAS  PubMed  Google Scholar 

  26. Gilmore MJ, Hamon MD, Prentice HG et al. Failure of purged autologous bone marrow transplantation in high risk acute lymphoblastic leukaemia in first complete remission Bone Marrow Transplant 1991 8: 19–26

    CAS  PubMed  Google Scholar 

  27. Billett AL, Sallan SE . Autologous bone marrow transplantation in childhood acute lymphoid leukemia with use of purging Am J Pediatr Hematol Oncol 1993 15: 162–168

    Article  CAS  PubMed  Google Scholar 

  28. Uckun FM, Kersey JH, Haake R et al. Pretransplantation burden of leukemic progenitor cells as a predictor of relapse after bone marrow transplantation for acute lymphoblastic leukemia New Engl J Med 1993 329: 1296–1301

    Article  CAS  PubMed  Google Scholar 

  29. Jones RJ, Vogelsang GB, Hess AD et al. Induction of graft-versus-host disease after autologous bone marrow transplantation Lancet 1989 1: 754–757

    Article  CAS  PubMed  Google Scholar 

  30. Geller RB, Esa AH, Beschorner WE et al. Successful in vitro graft-versus-tumor effect against an Ia-bearing tumor using cyclosporine-induced syngeneic graft-versus-host disease in the rat Blood 1989 74: 1165–1171

    CAS  PubMed  Google Scholar 

  31. Billett A, Ritz J . Hematopoietic cell transplantation for acute lymphoblastic leukemia. In: Thomas E, Blume K, Forman S (eds) Autologous Hematopoietic Cell Transplantation Blackwell Science: Malden, MA 1999 978–989

    Google Scholar 

  32. Buhrer C, Hartmann R, Fengler R et al. Superior prognosis in combined compared to isolated bone marrow relapses in salvage therapy of childhood acute lymphoblastic leukemia Med Pediatr Oncol 1993 21: 470–476

    Article  CAS  PubMed  Google Scholar 

  33. Colleselli P, Dini G, Andolina M et al. Autologous bone marrow transplantation for acute lymphoblastic leukemia: the high-dose vincristine study of AIEOP BMT group Bone Marrow Transplant 1991 3: 28–30

    Google Scholar 

  34. Herve P, Labopin M, Plouvier E et al. Autologous bone marrow transplantation for childhood acute lymphoblastic leukemia: a European Study. EBMT working party on ABMT Bone Marrow Transplant 1991 8: 76–79

    PubMed  Google Scholar 

  35. Rivera GK, Buchanan G, Boyett JM et al. Intensive retreatment of childhood acute lymphoblastic leukemia in first bone marrow relapse. A Pediatric Oncology Group Study New Engl J Med 1986 315: 273–278

    Article  CAS  PubMed  Google Scholar 

  36. Powles R, Mehta J, Singhal S et al. Autologous bone marrow or peripheral blood stem cell transplantation followed by maintenance chemotherapy for adult acute lymphoblastic leukemia in first remission: 50 cases from a single center Bone Marrow Transplant 1995 16: 241–247

    CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Lisa Bozenhard-Froncek and Shaunta Evans for secretarial assistance and Linda Rahl for her editorial support. We would also like to thank Dr Leonard Sender for his review and suggestions for this manuscript. We would also like to thank Roche Pharmaceuticals for kindly providing Roferon. This work was supported by grants from the Pediatric Cancer Research Foundation, The Walden W and Jean Young Shaw Foundation, and the Elsa U Pardee Foundation.

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Houtenbos, I., Bracho, F., Davenport, V. et al. Autologous bone marrow transplantation for childhood acute lymphoblastic leukemia: a novel combined approach consisting of ex vivo marrow purging, modulation of multi-drug resistance, induction of autograft vs leukemia effect, and post-transplant immuno- and chemotherapy (PTIC). Bone Marrow Transplant 27, 145–153 (2001). https://doi.org/10.1038/sj.bmt.1702750

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