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Prognosis in AML

Multivariate analysis of prognostic factors in patients with refractory and relapsed acute myeloid leukemia undergoing sequential high-dose cytosine arabinoside and mitoxantrone (S-HAM) salvage therapy: relevance of cytogenetic abnormalities

Leukemia volume 14, pages 226–231 (2000)Cite this article

Abstract

To improve the basis for the stratification of patients with refractory and relapsed acute myeloid leukemia (AML) univariate and multivariate analyses of prognostic factors were performed in 254 patients (median age 50 years, range 18–74) undergoing S-HAM salvage chemotherapy during two consecutive prospective trials of the German AML Cooperative Group. In a multivariate analysis, duration of the first complete remission (CR) was the only factor associated with time to treatment failure (P = 0.0223). Disease-free survival was influenced by a short duration of the first CR of less than 6 months (P = 0.0001), WBC (P = 0.0018), blast count (P = 0.0037), and neutrophil count (P = 0.0119). The achievement of CR was related to the hemoglobin level only (P = 0.0457), the early death rate was related to age only (P = 0.0109), and survival was related to the bilirubin level only (P = 0.0166). In the subgroup of 104 patients in whom additional karyotype analyses were performed prior to first-line therapy unfavorable chromosome abnormalities were associated with a lower CR rate (univariate analysis, P = 0.0342; CR 24% vs 53%) and were the only factor related to survival. These analyses warrant the further evaluation of the impact of cytogenetic abnormalities on the outcome of patients with advanced AML in order to improve the characterization according to duration of first CR and to WBC of distinct subgroups of patients with differing prognoses as a basis for stratification in future trials.

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References

  1. Russell NH . Biology of acute leukaemia Lancet 1997 349: 118–122

    Article  CAS  Google Scholar 

  2. Bloomfield CD, Lawrence D, Byrd JC, Carroll A, Pettenati MJ, Tantravahi R, Patil SR, Davey FR, Berg DT, Schiffer CA, Arthur DC, Mayer RJ . Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype Cancer Res 1998 58: 4173–4179

    CAS  PubMed  Google Scholar 

  3. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, Rees J, Hann I, Stevens R, Burnett A, Goldstone A . The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties Blood 1998 92: 2322–2333

    CAS  PubMed  Google Scholar 

  4. Mrozek K, Heinonen K, Lawrence D, Carroll AJ, Koduru PR, Rao KW, Strout MP, Hutchison RE, Moore JO, Mayer RJ, Schiffer CA, Bloomfield CD . Adult patients with de novo acute myeloid leukemia and t(9; 11)(p22;q23) have a superior outcome to patients with other translocations involving band 11q23: a cancer and leukemia group B study Blood 1997 90: 4532–4538

    CAS  PubMed  Google Scholar 

  5. Dreyling MH, Schrader K, Fonatsch C, Schlegelberger B, Haase D, Schoch C, Ludwig W, Loffler H, Buchner T, Wormann B, Hiddemann W, Bohlander SK . MLL and CALM are fused to AF10 in morphologically distinct subsets of acute leukemia with translocation t(10;11): both rearrangements are associated with a poor prognosis Blood 1998 91: 4662–4667

    CAS  PubMed  Google Scholar 

  6. Fenaux P, Le Deley MC, Castaigne S, Archimbaud E, Chomienne C, Link H, Guerci A, Duarte M, Daniel MT, Bowen D et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group Blood 1993 82: 3241–3249

    CAS  PubMed  Google Scholar 

  7. Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A, Shepherd L, Willman C, Bloomfield CD, Rowe JM, Wiernik PH . All-trans-retinoic acid in acute promyelocytic leukemia (see comments) (published erratum appears in New Engl J Med 1997 Nov 27; 337(22):1639) New Engl J Med 1997 337: 1021–1028

    Article  CAS  Google Scholar 

  8. Lo Coco F, Nervi C, Avvisati G, Mandelli F . Acute promyelocytic leukemia: a curable disease Leukemia 1998 12: 1866–1880

    Article  CAS  Google Scholar 

  9. Schoch C, Haferlach T, Haase D, Fonatsch C, Schlegelberger B, Sauerland MC, Loffler H, Staib P, Wormann B, Buchner T, Hiddemann W, the German AML Cooperative Group . Complex chromosome aberrations in patients with de novo AML are associated with a very poor prognosis despite intensive treatment: a study of 90 patients Blood 1997 90: 62a

    Google Scholar 

  10. Hiddemann W, Martin WR, Sauerland CM, Heinecke A, Buchner T . Definition of refractoriness against conventional chemotherapy in acute myeloid leukemia: a proposal based on the results of retreatment by thioguanine, cytosine arabinoside, and daunorubicin (TAD 9) in 150 patients with relapse after standardized first line therapy Leukemia 1990 4: 184–188

    CAS  PubMed  Google Scholar 

  11. Estey E . Treatment of refractory AML Leukemia 1996 10: 932–936

    CAS  PubMed  Google Scholar 

  12. Keating MJ, Kantarjian H, Smith TL, Estey E, Walters R, Andersson B, Beran M, McCredie KB, Freireich EJ . Response to salvage therapy and survival after relapse in acute myelogenous leukemia J Clin Oncol 1989 7: 1071–1080

    Article  CAS  Google Scholar 

  13. Kern W, Schleyer E, Unterhalt M, Wormann B, Buchner T, Hiddemann W . High antileukemic activity of sequential high dose cytosine arabinoside and mitoxantrone in patients with refractory acute leukemias. Results of a clinical phase II study Cancer 1997 79: 59–68

    Article  CAS  Google Scholar 

  14. Kern W, Schoch C, Haferlach T, Braess J, Unterhalt M, Wormann B, Buchner T, Hiddemann W . Significance of cytogenetic abnormalities in a multivariate analysis of prognostic factors in patients with refractory and relapsed acute myeloid leukemia Blood 1998 92: 78a

    Google Scholar 

  15. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C . Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French–American–British Cooperative Group Ann Intern Med 1985 103: 620–625

    Article  CAS  Google Scholar 

  16. Buchner T, Urbanitz D, Hiddemann W, Ruhl H, Ludwig WD, Fischer J, Aul HC, Vaupel HA, Kuse R, Zeile G, Nowrousian MR, Konig HJ, Walter M, Wendt FC, Sodomann H, Hossfeld DK, von Paleske A, Loffler H, Gassmann W, Hellriegel KP, Fulle HH, Lunscken C, Emmerich B, Pralle H, Pees HW, Pfreundschuh M, Bartels H, Koeppen KM, Schwerdtfeger R, Donhuijsen-Ant R, Mainzer K, Bonfert B, Koppler H, Zurborn KH, Ranft K, Thiel E, Heinecke A . 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 1985 3: 1583–1589

    Article  CAS  Google Scholar 

  17. Buchner T, Hiddemann W, Wormann B, Loffler H, Maschmeyer G, Hossfeld D, Ludwig WD, Nowrousian M, Aul C, Schaefer UW, Sauerland C, Heinecke A . Long-term effects of prolonged maintenance and of very early intensification chemotherapy in AML: data from AMLCG Leukemia 1992 6: (Suppl. 2) 68–71

    PubMed  Google Scholar 

  18. Kern W, Aul C, Maschmeyer G, Schönrock-Nabulsi R, Ludwig WD, Bartholomaus A, Bettelheim P, Wormann B, Buchner T, Hiddemann W, for the German AML Cooperative Group . Superiority of high-dose over intermediate-dose cytosine arabinoside in the treatment of patients with high-risk acute myeloid leukemia: results of a age-adjusted prospective randomized comparison Leukemia 1998 12: 1049–1055

    Article  CAS  Google Scholar 

  19. Kern W, Behre G, Rudolf T, Kerkhoff A, Grote-Metke A, Eimermacher H, Kubica U, Wormann B, Buchner T, Hiddemann W, for the German AML Cooperative Group . Failure of fluconazole prophylaxis to reduce mortality and the requirement of systemic amphotericin B therapy during treatment for refractory acute myeloid leukemia: results of a prospective randomized phase III study Cancer 1998 83: 291–301

    Article  CAS  Google Scholar 

  20. Patt YZ, Peters RE, Chuang VP, Wallace S, Mavligit G . Effective retreatment of patients with colorectal cancer and liver metastases Am J Med 1983 75: 237–240

    Article  CAS  Google Scholar 

  21. Yates J, Glidewell O, Wiernik P, Cooper MR, Steinberg D, Dosik H, Levy R, Hoagland C, Henry P, Gottlieb A, Cornell C, Berenberg J, Hutchison JL, Raich P, Nissen N, Ellison RR, Frelick R, James GW, Falkson G, Silver RT, Haurani F, Green M, Henderson E, Leone L, Holland JF . Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study Blood 1982 60: 454–462

    CAS  PubMed  Google Scholar 

  22. Kaplan EL, Meier P . Nonparametric estimation from incomplete estimations Am Stat Assoc J 1958 53: 457–481

    Article  Google Scholar 

  23. Schoch C, Haase D, Fonatsch C, Haferlach T, Loffler H, Schlegelberger B, Hossfeld DK, Becher R, Sauerland MC, Heinecke A, Wormann B, Buchner T, Hiddemann W . The significance of trisomy 8 in de novo acute myeloid leukaemia: the accompanying chromosome aberrations determine the prognosis. German AML Cooperative Study Group Br J Haematol 1997 99: 605–611

    Article  CAS  Google Scholar 

  24. Schoch C, Haase D, Haferlach T, Gudat H, Buchner T, Freund M, Link H, Lengfelder E, Wandt H, Sauerland MC, Loffler H, Fonatsch C . Fifty-one patients with acute myeloid leukemia and translocation t(8;21)(q22;q22): an additional deletion in 9q is an adverse prognostic factor Leukemia 1996 10: 1288–1295

    CAS  PubMed  Google Scholar 

  25. Schoch C, Haase D, Haferlach T, Freund M, Link H, Lengfelder E, Loffler H, Buchner T, Fonatsch C . Incidence and implication of additional chromosome aberrations in acute promyelocytic leukaemia with translocation t(15;17)(q22;q21): a report on 50 patients Br J Haematol 1996 94: 493–500

    Article  CAS  Google Scholar 

  26. Buchner T, Hiddemann W, Wormann B et al. Threapeutic outcome in AML is mainly determined by cytogenetics, LDH in serum, early response and, in a poor risk subgroup, by intensified induction treatment Blood 1997 90: 504a

    Google Scholar 

  27. Byrd JC, Lawrence D, Arthur DC, Pettenati MJ, Tantravahi R, Qumsiyeh M, Stamberg J, Davey FR, Schiffer CA, Bloomfield CD . Patients with isolated trisomy 8 in acute myeloid leukemia are not cured with cytarabine-based chemotherapy: results from Cancer and Leukemia Group B 8461 Clin Cancer Res 1998 4: 1235–1241

    CAS  PubMed  Google Scholar 

  28. Bloomfield CD, Shuma C, Regal L, Philip PP, Hossfeld DK, Hagemeijer AM, Garson OM, Peterson BA, Sakurai M, Alimena G, Berger R, Rowley JD, Ruutu T, Mitelman F, Dewald GW, Swansbury J . Long-term survival of patients with acute myeloid leukemia: a third follow-up of the Fourth International Workshop on Chromosomes in Leukemia Cancer 1997 80: 2191–2198

    Article  CAS  Google Scholar 

  29. Lowenberg B, Suciu S, Archimbaud E, Ossenkoppele G, Verhoef GE, Vellenga E, Wijermans P, Berneman Z, Dekker AW, Stryckmans P, Schouten H, Jehn U, Muus P, Sonneveld P, Dardenne M, Zittoun R . Use of recombinant GM-CSF during and after remission induction chemotherapy in patients aged 61 years and older with acute myeloid leukemia: final report of AML-11, a phase III randomized study of the Leukemia Cooperative Group of European Organisation for the Research and Treatment of Cancer and the Dutch Belgian Hemato-Oncology Cooperative Group Blood 1997 90: 2952–2961

    CAS  PubMed  Google Scholar 

  30. Archimbaud E, Thomas X, Leblond V, Michallet M, Fenaux P, Cordonnier C, Dreyfus F, Troussard X, Jaubert J, Travade P et al. Timed sequential chemotherapy for previously treated patients with acute myeloid leukemia: long-term follow-up of the etoposide, mitoxantrone, and cytarabine-86 trial (see comments) J Clin Oncol 1995 13: 11–18

    Article  CAS  Google Scholar 

  31. Archimbaud E, Leblond V, Fenaux P, Dombret H, Cordonnier C, Dreyfus F, Cony Makhoul P, Tilly H, Troussard X, Auzanneau G, Thomas X, Ffrench M, Marie JP . Timed sequential chemotherapy for advanced acute myeloid leukemia Hematol Cell Ther 1996 38: 161–167

    Article  CAS  Google Scholar 

  32. Montillo M, Mirto S, Petti MC, Latagliata R, Magrin S, Pinto A, Zagonel V, Mele G, Tedeschi A, Ferrara F . Fludarabine, cytarabine, and G-CSF (FLAG) for the treatment of poor risk acute myeloid leukemia Am J Hematol 1998 58: 105–109

    Article  CAS  Google Scholar 

  33. Sierra J, Granena A, Bosch F, Carreras E, Marti JM, Urbano Ispizua A, Rovira M, Rozman C . Mitoxantrone and intermediate-dose cytosine arabinoside for poor-risk acute leukemias: response to treatment and factors influencing outcome Hematol Oncol 1992 10: 301–309

    Article  CAS  Google Scholar 

  34. Harousseau JL, Milpied N, Briere J, Desablens B, Ghandour C . Mitoxantrone and intermediate-dose cytarabine in relapsed or refractory acute myeloblastic leukemia Nouv Rev Fr Hematol 1990 32: 227–230

    CAS  PubMed  Google Scholar 

  35. Smits P, Schoots L, de Pauw BE, de Witte T, Holdrinet RS, Janssen JT, Haanen C . Prognostic factors in adult patients with acute leukemia at first relapse Cancer 1987 59: 1631–1634

    Article  CAS  Google Scholar 

  36. Herzig RH, Lazarus HM, Wolff SN, Phillips GL, Herzig GP . High-dose cytosine arabinoside therapy with and without anthracycline antibiotics for remission reinduction of acute nonlymphoblastic leukemia J Clin Oncol 1985 3: 992–997

    Article  CAS  Google Scholar 

  37. Hiddemann W, Kreutzmann H, Straif K, Ludwig WD, Mertelsmann R, Donhuijsen Ant R, Lengfelder E, Arlin Z, Buchner T . High-dose cytosine arabinoside and mitoxantrone: a highly effective regimen in refractory acute myeloid leukemia Blood 1987 69: 744–749

    CAS  PubMed  Google Scholar 

  38. Walters RS, Kantarjian HM, Keating MJ, Plunkett WK, Estey EH, Andersson B, Beran M, McCredie KB, Freireich EJ . Mitoxantrone and high-dose cytosine arabinoside in refractory acute myelogenous leukemia Cancer 1988 62: 677–682

    Article  CAS  Google Scholar 

  39. Martiat P, Ghilain JM, Ferrant A, Doyen C, Delannoy A, Chatelain C, Bosly A, Michaux JL, Sokal G . High-dose cytosine arabinoside and amsacrine or mitoxantrone in relapsed and refractory acute myeloid leukaemia: a prospective randomized study Eur J Haematol 1990 45: 164–167

    Article  CAS  Google Scholar 

  40. Carella AM, Carlier P, Pungolino E, Resegotti L, Liso V, Stasi R, Montillo M, lacopino P, Mirto S, Pagano L et al. Idarubicin in combination with intermediate-dose cytarabine and VP-16 in the treatment of refractory or rapidly relapsed patients with acute myeloid leukemia. The GIMEMA Cooperative Group Leukemia 1993 7: 196–199

    CAS  PubMed  Google Scholar 

  41. Spadea A, Petti MC, Fazi P, Vegna ML, Arcese W, Avvisati G, Aloe Spiriti MA, Latagliata R, Meloni G, Testi AM et al. Mitoxantrone, etoposide and intermediate-dose Ara-C (MEC): an effective regimen for poor risk acute myeloid leukemia Leukemia 1993 7: 549–552

    CAS  PubMed  Google Scholar 

  42. Vogler WR, McCarley DL, Stagg M, Bartolucci AA, Moore J, Martelo O, Omura GA . A phase III trial of high-dose cytosine arabinoside with or without etoposide in relapsed and refractory acute myelogenous leukemia. A Southeastern Cancer Study Group trial Leukemia 1994 8: 1847–1853

    CAS  PubMed  Google Scholar 

  43. Garson OM, Hagemeijer A, Sakurai M, Reeves BR, Swansbury GJ, Williams GJ, Alimena G, Arthur DC, Berger R, de la Chapelle A et al. Cytogenetic studies of 103 patients with acute myelogenous leukemia in relapse Cancer Genet Cytogenet 1989 40: 187–202

    Article  CAS  Google Scholar 

  44. Kern W, Schoch C, Fonatsch C, Heinecke A, Wormann B, Buchner T, Hiddemann W . Treatment of acute myeloid leukemia in the elderly Home Health Care Consultant 1999 6: 2–13

    Google Scholar 

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Authors and Affiliations

  1. Department of Medicine III, University Hospital Großhadern, Ludwig-Maximilians-University, München, Germany

    W Kern, C Schoch, T Haferlach, J Braess, M Unterhalt & W Hiddemann

  2. Department of Medicine, City Hospital, Braunschweig, Germany

    B Wörmann

  3. Department of Medicine A, Westfälische-Wilhelms-University, Münster, Germany

    T Büchner

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Kern, W., Schoch, C., Haferlach, T. et al. Multivariate analysis of prognostic factors in patients with refractory and relapsed acute myeloid leukemia undergoing sequential high-dose cytosine arabinoside and mitoxantrone (S-HAM) salvage therapy: relevance of cytogenetic abnormalities. Leukemia 14, 226–231 (2000). https://doi.org/10.1038/sj.leu.2401668

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