Myeloablative Chemotherapy and Peripheral Blood Stem Cell Transplantation vs. Consolidation Therapy of Acute Myelogenous Leukemia in First Remission

  • A. Reichle
  • R. Andreesen
Conference paper
Part of the Haematology and Blood Transfusion / Hämatologie und Bluttransfusion book series (HAEMATOLOGY, volume 39)

Abstract

Historical data about dose intensity during induction and/or consolidation treatment as well as the evaluation of randomized clinical trials comparing different dose-levels of anthracyclines or Ara C demonstrate a close dose-response relationship in terms of CR rate and/or survival. However, repetitive application of submyeloblative regimens results in prolonged and severe therapy-associated pancytopenia. On the other hand, only few patients (17 to 37%) with HLA-identical siblings may be treated with allogeneic bone marrow transplantation (BMT). New dose-intensification concepts during consolidation for patients up to 60 years are now under evaluation using myeloablative or sequentially applied submyelo ablative consolidation cycles supported with autologous peripheral blood stem cells (PBSC), which may be routinely collected in 1st CR during subsequent consolidation cycles. These PBSC give rise to leucocyte reconstitution about 10 days post transplantation (> 1.0/nl) as well as to long-term hematopoietic recovery. Stem cell collection and transplantation offers new insights in leukemic disease biology: stem cell kinetics in the peripheral blood significantly differ from that of lymphomas and solid tumors. Additionally, chemotherapy may produce both irreversible as well as reversible stem cell damage. Further, studies to determine the clinical significance of minimal residual disease are of major importance.The risk of reinfusion of residual leukemic cells seems to be of minor relevance to autologous transplantation than control of the disease in the host:
  1. 1.

    Myeloablative chemotherapy (CT) in 2nd CR supported with autologous BM collected in 1st CR shows significantly superior long-term results than conventional CT.

     
  2. 2.

    Results of allogeneic BMT in syngeneic twins in 1st CR compare with autologous BMT or PBSCT.

     
  3. 3.

    Superior survival data of autologous transplantation concepts are observed when standard CT with relatively low dose-intensity has been used and outcome seems to be at least equivalent when compared to highly dose-intensive standard treatment schedules.

     
  4. 4.

    Risk factors for standard CT seem to be the same for autologous and allogeneic transplantation.

     
Nevertheless, gene marking experiments have shown that transplantation of dono-genic leukemia cells remains a possible risk. When myeloablative CT supported with autologous PBSC is used as late consolidation more than 80% of the relapses are observed during the first year post transplantation. Thus, myeloablative chemotherapy results in another relapse behaviour compared with standard CT probably indicating better disease control in standard risk groups. This observation is supported by the analysis of risk factors in relapsing patients after myeloablative CT supported with PBSC. In conclusion, PBSC supported dose-intensification during consolidation seems to be a feasible treatment concept which may result in less severe therapy-associated side effects due to shortened pancytopenia and an improved leukemia control.

Keywords

Lymphoma Leukemia Oncol Cyclophosphamid Stein 

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References

  1. 1.
    Rai KR, Hollan JR, Glidewell OJ, Weinberg V, Brunner K, Obrecht JP, Preisler HD, Nawabi IW, Prager D, Carey RW, Cooper MR, Haurani F, Hutchison JL, Silver RT, Falkson G, Wiernik P, Hoagland HC, Bloomfield CD, James GW, Gottlieb A, Ramanan SV, Blom J, Nissen NI, Bank A, Ellison RR, Kung F, Henry P, McIntyre OR, Kaan SK (1981) Treatment of acute myelocytic leukemia: a study by Cancer and Leukemia Group B. Blood 58: 1203–1212PubMedGoogle Scholar
  2. 2.
    Mayer RI, Schiffer CA, Peterson BA, Budman DR, Silver RT, Rai KR, Cornwell GG, Ellison RR, Maguire M, Berg DT, et al. (1992) Intensive post-remission therapy in adults with acute nonlymphocytic leukemia using various dose schedules of ara C: a progress report from the CALGB. Cancer and Leukemia Group B. Semin Oncol 14: 25–31Google Scholar
  3. 3.
    Mayer RJ, Davis RB, Schiffer CA, Berg DT, Sarno E, Frei E 3d (1992) Intensive postremission the-rapy with Ara-C in adults with acute myeloid leukemia: initial results of a CALGB phase III trial. Cancer and Leukemia Group B. Leukemia 6 Suppl 2: 66–67Google Scholar
  4. 4.
    Cassileth PA, Andersen JW, Bennett JM, Harrington DP, Hines JD, Lazarus HM, Mazza JJ, McGlave PP, O’Connell MJ, Paietta E, et al. (1992) Escalating the intensity of postremission therapy improves the outcome in acute myeloid leukemia: the ECOG experience. Leukemia 6 Suppl 2: 116–119Google Scholar
  5. 5.
    Vogler WR, Winton EF, Gordon DS, Raney MR, Go B, Meyer L (1984) A randomized comparison of postremission therapy in acute myelogenous leukemia: a Southeastern Cancer Study Group trial. Blood 63: 1039–1045PubMedGoogle Scholar
  6. 6.
    Jehn U, Zittoun R, Suciu S (1990) A randomised comparison of intensive maintenance treatment for adult acute myelogenous leukemia using either cyclic alternating drugs or repeated courses of the induction type chemotherapy AML trial of the EORTC Leukemia Cooperative Group. Hematol Bluttransfus 33: 272–284Google Scholar
  7. 7.
    Büchner T, Urbanitz D, Hiddemann W (1995) Intensified induction and consolidation with or without maintenance chemotherapy for acute myeloid leukemia (AML): two multicenter studies of the German AML Cooperative Group. J Clin Oncol 3: 1583–1589Google Scholar
  8. 8.
    Jehn U, Zittoun R, Suciu S Fiere D, Haanen C, Peetermans M, Lowenberg B, Willemze R, Solbu G, Stryckmans P (1992) Intensive consolidation chemotherapy versus standard consolidation, maintenance in acute myelogenous leukemia (AML) in first remission. An EORTC/GIMEMA phase III trial (AML 8 B). The EORTC Leukemia Cooperative Group and the GIMEMA Group. Leukemia 6 Suppl 2: 76–7Google Scholar
  9. 9.
    Rees JK, Gray RG, Swirsky D, Hayhoe FG (1986) Principal results of the Medical Research Council’s 8th acute myeloid leukaemia trial. Lancet 2: 1236–1241PubMedCrossRefGoogle Scholar
  10. 10.
    Vogler WR (1992) Strategies in the treatment of acute myelogenous leukemia. Leuk Res 16: 1143–1153PubMedCrossRefGoogle Scholar
  11. 11.
    Büchner T, Hiddemann W, Wörmann B (1992) Longterm effects of prolonged maintenance and of very early intensification chemotherapy in AML: data from AMLCG. Leukemia 6 Suppl 2: 68–71Google Scholar
  12. 12.
    Bishop JF, Matthews JP, Young GA, Szer J, Gillett A, Joshua D, Bradstock K, Enno A, Wolf MM, Fox R, Cobcroft R, Herrmann R, Van Der Weyden M, Lowenthal RM, Page F, Garson OM, Juneja S (1996) A randomized study of high dose cytarabine in induction in acute myeloid leukemia. Blood 87: 1710–1717PubMedGoogle Scholar
  13. 13.
    Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, Omura GA, Moore JO (1994) Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 331: 896–903PubMedCrossRefGoogle Scholar
  14. 14.
    Weick JK, Kopecky KJ, Appelbaum FR et al. (1996) A randomized investigation of high dose versus standard dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group Study. Blood 88: 2841–2851PubMedGoogle Scholar
  15. 15.
    Anderlini P, Luna M, Kantarjian HM, O’Brien S, Pierce S, Keating MJ, Estey EH (1996) Causes of initial remission induction failure in patients with acute myeloid leukemia and myelodysplastic syndromes. Leukemia 10: 600–605PubMedGoogle Scholar
  16. 16.
    Cassileth PA, Lynch E, Hines JD, Oken MM, Mazza JJ, Bennett JM, McGlave PB, Edelstein M, Harrington DP, O’Connell MJ (1992) Varying intensity of postremission therapy in acute myeloid leukemia. Blood 79: 1924–1930PubMedGoogle Scholar
  17. 17.
    Vellenga E, Young DC, Wagner K, Wiper D, Ostapovicz-D, Griffin JD (1987) The effects of GM CSF and G CSF in promoting growth of dono-genic cells in acute myeloblastic leukemia. Blood 69: 1771–1777Google Scholar
  18. 18.
    Ohno R, Hiraoka A, Tanimoto M, Asou-N, Kuriyama K,Kobayashi T, Yoshida M, Teshima H, Saito H, Fujimoto K (1993) No increase of leukemia relapse in newly diagnosed patients with acute myeloid leukemia who received granulocyte colony stimulating factor for life threatening infections during remission, induction and consolidation therapy. Blood 81: 561–566Google Scholar
  19. 19.
    Estey E, Thall P, Andreeff M, Beran M, Kantarjian H, O’Brien S, Escudier S, Robertson LE, Koller C, Kornblau Set al. (1994) Use of granulocyte colony stimulating factor before, during, and after fludarabine plus cytarabine induction therapy of newly diagnosed acute myelogenous leukemia or myelodysplastic syndromes: comparison with fludarabine plus cytarabine without granulocyte stimulating factor. J Clin Oncol 12: 671–678PubMedGoogle Scholar
  20. 20.
    Heil G, Hoelzer D, Sanz MA, (1995) Results of a randomized double blind placebo controlled phase III study of filgrastim in remission, induction and early consolidation therapy for adults with de novo acute myeloid leukemia. Blood 86: 267aGoogle Scholar
  21. 21.
    Crawford J, George M (1995) The role of hematopoietic growth factors in support of ifosfamide/carboplatin/etoposide chemotherapy. Sem Oncol 22: 18–22Google Scholar
  22. 22.
    Zittoun R, Mandelli F, Willemze R, de Witte T; Labar B; Resegotti L; Leoni F; Damasio E; Visani G; Papa G; et al. (1995) Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med 332: 217–223PubMedCrossRefGoogle Scholar
  23. 23.
    Reichle A, Bross K, Reng M (1995) Sequential mobilization of CD 34 positive cells during induction and consolidation treatment in acute myelogenous leukemia (AML). Onkologie. International Journal for Cancer Research and Treatment 18: 13Google Scholar
  24. 24.
    Mc Millan AK, Goldstone AH, Linch DC (1990) High dose chemotherapy and autologous bone marrow transplantation in acute myeloid leukemia. Blood 76: 480–488Google Scholar
  25. 25.
    Stein AS, O’Donnell MR, Chai A, Schmidt GM, Nademanee A, Parker PM, Smith EP, Snyder DS, Molina A, Stepan DE, Spielberger R, Somlo G, Margolin KA, Vora N, Lipsett J, Lee J, Niland J, Forman SJ (1996) In vivo purging with high dose cytarabine followed by high dose chemoradio therapy and reinfusion of unpurged bone 36. marrow for adult acute myelogenous leukemia in first complete remission. J Clin Oncol 14: 2206–2216PubMedGoogle Scholar
  26. 26.
    Linker CA, Ries CA, Damon LE, Rugo HS, Wolf JL (1993)Autologous bone marrow transplantation for acute myeloid leukemia using busulfan plus etoposide as a preparative regimen. Blood 81: 311–318Google Scholar
  27. 27.
    Cassileth PA, Andersen J, Lazarus HM, Colvin OM, Bennett JM, Stadtmauer EA, Kaizer H, Weiner RS, Edelstein M, Oken MM (1993) Autologous bone marrow transplantation in acute myeloid leukemia in first remission. J Clin On-col 11: 314–319Google Scholar
  28. 28.
    Löwenberg B, Verdonck LJ, Dekker AW, Willemze R, Zwaan FE, de Planque M, Abels J, Sonneveld P, van der Lelie J, Goudsmit R et al. (1990) Autologous bone marrow transplantation in acute myeloid leukemia in first remission: results of a Dutch prospective study. J Clin Oncol 8: 287–294PubMedGoogle Scholar
  29. 29.
    Sanz MA, de la Rubia J, Sanz GF, Martin G, Martinez J, Jarque I, Sempere A, Gomis F, Senent L, Soler MA et al. (1993) Busulfan plus cyclophosphamide followed by autologous blood stem cell transplantation for patients with acute myeloblastic leukemia in first complete remission: a report from a single institution. J Clin Oncol 11: 1661–1667PubMedGoogle Scholar
  30. 30.
    Lévy V, Rio B, Belhocine R (1996) Autologous stem cell transplantation (APSCT) with G CSF primed peripheral blood in acute myelogenous leukemia (AML) in first remission (CR). Blood 88: 238Google Scholar
  31. 31.
    Reichle A, Hennemann B, Meidenbauer N (1996) Peripheral blood stem cell transplantation (PBSCT) during consolidation treatment of de novo acute myelogenous leukemia. Blood 88: 287Google Scholar
  32. 32.
    Cahn JY, Labopin M, Mandelli F, Goldstone AH, Eberhardt K, Reiffers J, Ferrant A, Franklin I, Herve P, Gratwohl A et al. (1995) Autologous bone marrow transplantation for first remission acute myeloblastic leukemia in patients older than 50 years: a retrospective analysis of the European Bone Marrow Transplant Group. Blood 85: 575–579PubMedGoogle Scholar
  33. 33.
    Gale RP, Horowitz MM, Rees JK, Gray RG, Oken MM, Estey EH, Kim KM, Zhang MJ, Ash RC, Atkinson K, Champlin RE, Dicke KA, Gajewski JL, Goldman JM, Helbig W, Henslee Downey PS, Hinterberger W, Jacobsen N, Keating A, Klein JP, Marmont AM, Prentice HG, Reiffers J, Rimm AA, Bortin MM et al. (1996) Chemotherapy versus transplants for acute myelogenous leukemia in second remission. Leukemia 10: 13–19PubMedGoogle Scholar
  34. 34.
    Schiller G, Mittal Henkle A, Lill M (1995) Transplantation of autologous blood progenitor cells procured after high dose cytarabine/G CSF based consolidation for adults with acute myelogenous leukemia in first remission. Blood 86: 99aGoogle Scholar
  35. 35.
    Linker CA, Ries CA, Damon LE (1995) Autolo- 48. gnus stem cell transplantation for acute myeloid leukemia in first remission. Blood 86: 99aGoogle Scholar
  36. 36.
    Reiffers J, Korbling M, Labopin M, Gorin NC (1992) Autologous blood stem cell transplantation versus autologous bone marrow transplantation for acute myeloid leukemia in first remission: A retrospective analysis of the EBMT registry. Proc. Eur Bone Marrow Transplant p 107 (abstr 7)Google Scholar
  37. 37.
    Frassoni F, Labopin M, Gluckmann E (1996) Results of allogeneic bone marrow transplantation for acute leukemia have improved in Europe with time a report of the acute leukemia working party of the European group for blood and marrow transplantation (EBMT). Bone Marrow Transplant 17: 13–18PubMedGoogle Scholar
  38. 38.
    Labopin M, Gorin NC (1992) Autologous bone marrow transplantation in 2502 patients with acute leukemia in Europe: a retrospective study. Leukemia 6: 95–99PubMedGoogle Scholar
  39. 39.
    Brenner MK, Rill DR, Moen RC, Krance RA, Mirro J Jr, Anderson WF, Ihle JN (1993) Gene marking to trace origin of relapse after autologous bone marrow transplantation. Lancet 341: 85–86PubMedCrossRefGoogle Scholar
  40. 40.
    Brenner MK, Rill DR, Moen RC, Krance RA, Heslop HE, Mirro J Jr, Anderson WF, Ihle JN (1994) Gene marking and autologous bone marrow transplantation. Ann NY Acad Sci 716: 204–214PubMedCrossRefGoogle Scholar
  41. 41.
    Laporte JP, Douay L, Lopez M, Lab opin M, Jouet JP, Lesage S, Stachowiak J, Fouillard L, Isnard F, Noel Walter MP et al. (1994) One hundred twenty five adult patients with primary acute leukemia autografted with marrow purged by mafosfamide: A 10 year single institution experience. Blood 84: 3810–3818PubMedGoogle Scholar
  42. 42.
    Ball ED, Rybka WB (1993) Autologous bone marrow transplantation for adult acute leukemia. Hematol Oncol Clin North Am 7: 201–231 Fores R, Diez Martin JL, Briz M, Cabrera JR, San-juan I, Regidor C, Garcia Talavera J, Fernandez MN (1995) Donor leukocyte infusions for treatment of relapsed acute myeloid leukemia after allogeneic bone marrow transplantation. Bone Marrow Transplant 17: 439–441Google Scholar
  43. 43.
    Büchner T, Heinecke A (1996) The role of prognostic factors in acute myeloid leukemia. Leukemia 10: S28 - S29PubMedGoogle Scholar
  44. 44.
    Hiddemann W, Fonatsch C, Wörmann B (1995) Cytogenetic subgroups of AML and outcome from high dose versus conventional ara C therapy as part of double induction therapy. Blood 86, No 10: 267Google Scholar
  45. 45.
    Yaeger AM (1994) Autologous bone marrow transplantation for acute myeloid leukemia. In Forman SJ, Blume KG, Thomas ED (eds). Bone marrow transplantation. Bladewell Scientific Publications Oxford 709–730Google Scholar
  46. 46.
    Carella AM, Frassoni F, van Lint MT, Gualandi F, Occhini D, Carlier P, Pollicardo N, Ungolino E, Fagioli F, Santini G et al. (1992) Autologous and allogeneic bone marrow transplantation in acute myeloid leukemia in irst complete remission: an update of the Genoa experience with 159 patients. Ann Hematol 64: 128–131PubMedCrossRefGoogle Scholar
  47. 47.
    Carella AM, Frassoni F, van Lint MT, Gualandi F, Occhini D, Carlier P, Pollicardo N, Ungolino E, Fagioli F, Santini G et al. (1992) Autologous and allogeneic bone marrow transplantation in acute myeloid leukemia in irst complete remission: an update of the Genoa experience with 159 patients. Ann Hematol 64: 128–131PubMedCrossRefGoogle Scholar
  48. 48.
    Burnett AK, Tansey P, Watkins R, Alcorn M, Maharaj D, Singer CR, McKinnon S, Donald GA, Robertson AG (1984) Transplantation of unpurged autologous bone marrow in acute myeloid leukemia in 1 rst remission. Lancet 10: 1068–1070CrossRefGoogle Scholar
  49. 49.
    Beelen DW, Quabeck K, Graeven U, Sayer HG, Mahmoud HK, Schaefer UW (1989) Acute toxicity and first clinical results of intensive post induction therapy using a odified busulfan and cyclophosphamid regimen with autologous bone marrow rescue in first remission of acute myeloid leukemia. Blood 74: 1507–1516PubMedGoogle Scholar
  50. 50.
    Körbling M, Hunstein W, Fliedner TM, Cayeux S, Dorken B, Fehrentz D, Haas R, Ho AD, Keilholz U, Knauf W et al. (1989) Disease free survival after autologous bone marrow transplantation in patients with acute myelogenous leukemia. Blood 74: 1898–1904PubMedGoogle Scholar
  51. 51.
    Keating MJ, Smith TL, Kantarjian H, Cork A, Walters R, Trujillo JM, McCredie KB, Gehan EA, Freireich EJ (1988) Cytogenetic pattern in acute myelogenous leukemia: a major reproducible determinant of outcome. Leukemia 2: 403–412PubMedGoogle Scholar
  52. 52.
    Büchner T, Hiddemann W, Wörmann B (1996) Intensive consolidation versus prolonged maintenance following intensive induction and conventional consblidation in primary AML: A Study by AMLCG. Blood 88: 214aGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • A. Reichle
    • 1
  • R. Andreesen
    • 1
  1. 1.Department of Hematology and OncologyUniversity of RegensburgRegensburgGermany

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