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Karyotype instability between diagnosis and relapse in 117 patients with acute myeloid leukemia: implications for resistance against therapy

Leukemia volume 16, pages 2084–2091 (2002)Cite this article

Abstract

The instability of the karyotype may play a role in the development of refractoriness of acute myeloid leukemia (AML) to anti-leukemic therapy. Therefore, in the current study cytogenetic analyses were performed in 117 patients with AML both at diagnosis and at relapse. Changes in karyotype were observed in 38% (36% of initially normal karyotypes, 39% of initially aberrant karyotypes). An evolution of karyotype, ie the acquisition of further aberrations in addition to those present at diagnosis, occurred more frequently in patients with unfavorable karyotypes at diagnosis as compared to all others (60% vs 32%, P = 0.0095). The duration from initial diagnosis to relapse was significantly shorter in cases with an evolution of the aberrant karyotype as compared to cases with no changes in the aberrant karyotype between diagnosis and relapse or with solely regression of aberrations at relapse (9.2 ± 4.4 vs14.0 ± 8.5 months, P = 0.0081). In an additional analysis, another cohort of 120 patients with refractory and relapsed AML who were treated uniformly within the respective trial of the German AML Cooperative Group was analyzed cytogenetically at diagnosis and at relapse to further prove the prognostic impact of karyotype aberrations at relapse. Karyotypes were prognostically favorable, intermediate, unfavorable and not available in 8%, 50%, 17% and 25% at diagnosis and in 8%, 49%, 21% and 22% at relapse, respectively. Karyotype aberrations at diagnosis had no impact on response to therapy (P = 0.32) but influenced survival and event-free survival significantly (P = 0.03 and P = 0.02). In contrast, karyotype aberrations at relapse strongly influenced response to therapy (P = 0.05), survival (P = 0.01), and event-free survival (P = 0.002). These data suggest that the instability of the karyotype between diagnosis and relapse and thus karyotype aberrations at relapse in particular contribute to the refractoriness of AML to anti-leukemic therapy.

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References

  1. Rowley JD . Molecular genetics in acute leukemia Leukemia 2000 14: 513–517

    Article  CAS  PubMed  Google Scholar 

  2. Melnick A, Licht JD . Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia Blood 1999 93: 3167–3215

    CAS  PubMed  Google Scholar 

  3. Downing JR . The AML1-ETO chimaeric transcription factor in acute myeloid leukaemia: biology and clinical significance Br J Haematol 1999 106: 296–308

    Article  CAS  PubMed  Google Scholar 

  4. Goger M, Gupta V, Kim WY, Shigesada K, Ito Y, Werner MH . Molecular insights into PEBP2/CBF beta-SMMHC associated acute leukemia revealed from the structure of PEBP2/CBF beta Nat Struct Biol 1999 6: 620–623

    Article  CAS  PubMed  Google Scholar 

  5. Schoch C, Haferlach T, Haase D, Fonatsch C, Loffler H, Schlegelberger B, Staib P, Sauerland MC, Heinecke A, Buchner T, Hiddemann W . Patients with de novo acute myeloid leukaemia and complex karyotype aberrations show a poor prognosis despite intensive treatment: a study of 90 patients Br J Haematol 2001 112: 118–126

    Article  CAS  PubMed  Google Scholar 

  6. Buchner T, Hiddemann W, Wormann B, Loffler H, Gassmann W, Haferlach T, Fonatsch C, Haase D, Schoch C, Hossfeld D, Lengfelder E, Aul C, Heyll A, Maschmeyer G, Ludwig WD, Sauerland MC, Heinecke A . Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group Blood 1999 93: 4116–4124

    CAS  PubMed  Google Scholar 

  7. 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 

  8. Kern W, Schoch C, Haferlach T, Braess J, Unterhalt M, Wormann B, Buchner T, Hiddemann W . 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 2000 14: 226–231

    Article  CAS  PubMed  Google Scholar 

  9. Gale RP, Horowitz MM, Weiner RS, Ash RC, Atkinson K, Babu R, Dicke KA, Klein JP, Lowenberg B, Reiffers J . Impact of cytogenetic abnormalities on outcome of bone marrow transplants in acute myelogenous leukemia in first remission Bone Marrow Transplant 1995 16: 203–208

    CAS  PubMed  Google Scholar 

  10. Schneider E, Cowan KH, Bader H, Toomey S, Schwartz GN, Karp JE, Burke PJ, Kaufmann SH . Increased expression of the multidrug resistance-associated protein gene in relapsed acute leukemia Blood 1995 85: 186–193

    CAS  PubMed  Google Scholar 

  11. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C . Proposal for the recognition of minimally differentiated acute myeloid leukaemia (AML-MO) (see comments) Br J Haematol 1991 78: 325–329

    Article  CAS  PubMed  Google Scholar 

  12. 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  PubMed  Google Scholar 

  13. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C . A variant form of hypergranular promyelocytic leukemia (M3) (letter) Ann Intern Med 1980 92: 261

    Article  CAS  PubMed  Google Scholar 

  14. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C . Proposals for the classification of the acute leukaemias. French– American–British (FAB) co-operative group Br J Haematol 1976 33: 451–458

    Article  CAS  PubMed  Google Scholar 

  15. Kern W, Schoch C, Haferlach T, Braess J, Wormann B, Buchner T, Ludwig WD, Hiddemann W . Prognostic significance of cytogenetics at relapse in patients receiving sequential high-dose cytosine arabinoside and idarubicin (S-HAI) + fludarabine therapy for refractory and relapsed acute myeloid leukemia Blood 2000 96: 504a

    Google Scholar 

  16. 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  PubMed  Google Scholar 

  17. Schoch C, Bursch S, Kern W, Schnittger S, Hiddemann W, Haferlach T . Gain of an isochromosome 5p: a new recurrent chromosome abnormality in acute monoblastic leukemia Cancer Genet Cytogenet 2001 127: 85–88

    Article  CAS  PubMed  Google Scholar 

  18. Schnittger S, Schoch C, Kern W, Staib P, Wuchter C, Sauerland C, Serve H, Buchner T, Haferlach T, Hiddemann W . FLT3 length mutations in AML: correlation to cytogenetics, FAB-subtype, and prognosis in 652 patients Blood 2000 96: 826a

    Google Scholar 

  19. Schnittger S, Wormann B, Hiddemann W, Griesinger F . Partial tandem duplications of the MLL gene are detectable in peripheral blood and bone marrow of nearly all healthy donors Blood 1998 92: 1728–1734

    CAS  PubMed  Google Scholar 

  20. 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 (Suppl. 1): 504a

    Google Scholar 

  21. 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 

  22. 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  PubMed  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  PubMed  Google Scholar 

  24. 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 

  25. Rowley JD, Potter D . Chromosomal banding patterns in acute nonlymphocytic leukemia Blood 1976 47: 705–721

    CAS  PubMed  Google Scholar 

  26. Li YS, Khalid G, Hayhoe FG . Correlation between chromosomal pattern, cytological subtypes, response to therapy, and survival in acute myeloid leukaemia Scand J Haematol 1983 30: 265–277

    Article  CAS  PubMed  Google Scholar 

  27. Estey E, Keating MJ, Pierce S, Stass S . Change in karyotype between diagnosis and first relapse in acute myelogenous leukemia Leukemia 1995 9: 972–976

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  29. Testa JR, Mintz U, Rowley JD, Vardiman JW, Golomb HM . Evolution of karyotypes in acute nonlymphocytic leukemia Cancer Res 1979 39: 3619–3627

    CAS  PubMed  Google Scholar 

  30. Kantarjian HM, Keating MJ, Walters RS, McCredie KB, Freireich EJ . The characteristics and outcome of patients with late relapse acute myelogenous leukemia J Clin Oncol 1988 6: 232–238

    Article  CAS  PubMed  Google Scholar 

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  1. Ludwig-Maximilians-University, University Hospital Grosshadern, Dept. of Internal Medicine III, Muenchen, Germany

    W Kern, T Haferlach, S Schnittger, W Hiddemann & C Schoch

  2. Robert-Rössle-Klinik, Charité, Humbolt-University, Berlin, Germany

    WD Ludwig

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Kern, W., Haferlach, T., Schnittger, S. et al. Karyotype instability between diagnosis and relapse in 117 patients with acute myeloid leukemia: implications for resistance against therapy. Leukemia 16, 2084–2091 (2002). https://doi.org/10.1038/sj.leu.2402654

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