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Acute Leukemia

Cytogenetics and outcome of allogeneic transplantation in first remission of acute myeloid leukemia: the French pediatric experience

Abstract

We analyzed the impact of cytogenetics on 193 children enrolled in two successive French trials (LAME89/91 and ELAM02), who received hematopoietic stem cell transplantation during CR1. Detailed karyotype was available for 66/74 (89%) in LAME89/91 and 118/119 (99%) in ELAM02. Several karyotype and transplant characteristics differed according to therapeutic protocol: unfavorable karyotypes were more frequent in ELAM02 (36% vs 18%), pretransplant chemotherapy included high-dose cytarabine in ELAM02 and not in LAME89/91, IV replaced oral busulfan in the conditioning regimen, methotrexate was removed from post-transplant immunosuppression, and matched unrelated donor and cord blood transplantation were introduced. Five-year overall survival (OS) was 78.2% in LAME89 and 81.4% in ELAM02. OS was significantly lower for the unfavorable cytogenetic risk group in LAME89/91 when compared with intermediate and favorable groups (50% vs 90.6 and 86.4%, P=0.001). This difference was no longer apparent in ELAM02 (80.9% vs 71.3% and 5/5, respectively). Survival improvement for children with unfavorable karyotype was statistically significant (P=0.026) and was due to decrease in relapse risk. Five-year transplantation-related mortality was 6.75% in LAME89/91. In ELAM02, it was 3.2% for patients with a sibling donor and 10.9% with an unrelated donor or cord blood. We conclude that the outcome of children with unfavorable karyotype transplanted in CR1 has improved.

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References

  1. Hasle H . A critical review of which children with acute myeloid leukaemia need stem cell procedures. Br J Haematol 2014; 166: 23–33.

    Article  Google Scholar 

  2. Niewerth D, Creutzig U, Bierings MB, Kaspers GJ . A review on allogeneic stem cell transplantation for newly diagnosed pediatric acute myeloid leukemia. Blood 2010; 116: 2205–2214.

    Article  CAS  Google Scholar 

  3. Creutzig U, van den Heuvel-Eibrink MM, Gibson B, Dworzak MN, Adachi S, de Bont E et al. Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel. Blood 2012; 120: 3187–3205.

    Article  CAS  Google Scholar 

  4. Harrison CJ, Hills RK, Moorman AV, Grimwade DJ, Hann I, Webb DK et al. Cytogenetics of childhood acute myeloid leukemia: United Kingdom Medical Research Council Treatment trials AML 10 and 12. J Clin Oncol 2010; 28: 2674–2681.

    Article  Google Scholar 

  5. von Neuhoff C, Reinhardt D, Sander A, Zimmermann M, Bradtke J, Betts DR et al. Prognostic impact of specific chromosomal aberrations in a large group of pediatric patients with acute myeloid leukemia treated uniformly according to trial AML-BFM 98. J Clin Oncol 2010; 28: 2682–2689.

    Article  CAS  Google Scholar 

  6. Kolb HJ . Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 2008; 112: 4371–4383.

    Article  CAS  Google Scholar 

  7. Michel G, Leverger G, Leblanc T, Nelken B, Baruchel A, Landman-Parker J et al. Allogeneic bone marrow transplantation vs aggressive post-remission chemotherapy for children with acute myeloid leukemia in first complete remission. A prospective study from the French Society of Pediatric Hematology and Immunology (SHIP). Bone Marrow Transplant 1996; 17: 191–196.

    CAS  PubMed  Google Scholar 

  8. Perel Y, Auvrignon A, Leblanc T, Vannier JP, Michel G, Nelken B et al. Impact of addition of maintenance therapy to intensive induction and consolidation chemotherapy for childhood acute myeloblastic leukemia: results of a prospective randomized trial, LAME 89/91. Leucamie Aique Myeloide Enfant. J Clin Oncol 2002; 20: 2774–2782.

    Article  Google Scholar 

  9. Balgobind BV, Raimondi SC, Harbott J, Zimmermann M, Alonzo TA, Auvrignon A et al. Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood 2009; 114: 2489–2496.

    Article  CAS  Google Scholar 

  10. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010; 116: 354–365.

    Article  CAS  Google Scholar 

  11. Hasle H, Alonzo TA, Auvrignon A, Behar C, Chang M, Creutzig U et al. Monosomy 7 and deletion 7q in children and adolescents with acute myeloid leukemia: an international retrospective study. Blood 2007; 109: 4641–4647.

    Article  CAS  Google Scholar 

  12. Sandahl JD, Coenen EA, Forestier E, Harbott J, Johansson B, Kerndrup G et al. t(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients. Haematologica 2014; 99: 865–872.

    Article  Google Scholar 

  13. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114: 937–951.

    Article  CAS  Google Scholar 

  14. Michel G, Valteau-Couanet D, Gentet JC, Esperou H, Socie G, Mechinaud F et al. Weight-based strategy of dose administration in children using intravenous busulfan: clinical and pharmacokinetic results. Pediatr Blood Cancer 2012; 58: 90–97.

    Article  Google Scholar 

  15. Kaplan EL, Meier P . Nonparametric estimation from incomplete observations. J Am Statist Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  16. Cox DR . Regression models and life-tables. J R Stat Soc 1972; 34: 187–220.

    Google Scholar 

  17. Fine JP, Gray RJ . A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496–509.

    Article  Google Scholar 

  18. Gooley TA, Leisenring W, Crowley J, Storer BE . Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 1999; 18: 695–706.

    Article  CAS  Google Scholar 

  19. Horan JT, Alonzo TA, Lyman GH, Gerbing RB, Lange BJ, Ravindranath Y et al. Impact of disease risk on efficacy of matched related bone marrow transplantation for pediatric acute myeloid leukemia: the Children's Oncology Group. J Clin Oncol 2008; 26: 5797–5801.

    Article  Google Scholar 

  20. Kelly MJ, Horan JT, Alonzo TA, Eapen M, Gerbing RB, He W et al. Comparable survival for pediatric acute myeloid leukemia with poor-risk cytogenetics following chemotherapy, matched related donor, or unrelated donor transplantation. Pediatr Blood Cancer 2014; 61: 269–275.

    Article  CAS  Google Scholar 

  21. Klusmann JH, Reinhardt D, Zimmermann M, Kremens B, Vormoor J, Dworzak M et al. The role of matched sibling donor allogeneic stem cell transplantation in pediatric high-risk acute myeloid leukemia: results from the AML-BFM 98 study. Haematologica 2012; 97: 21–29.

    Article  CAS  Google Scholar 

  22. Michel G, Cunha R, Ruggeri A, O'Brien TA, Bittencourt H, Dalle JH et al. Unrelated cord blood transplantation for childhood acute myelogenous leukemia: The influence of cytogenetic risk group stratification. Leukemia 2015; 30: 1180–1183.

    Article  Google Scholar 

  23. Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia cancer and leukemia group B. N Engl J Med 1994; 331: 896–903.

    Article  CAS  Google Scholar 

  24. Lie SO, Abrahamsson J, Clausen N, Forestier E, Hasle H, Hovi L et al. Treatment stratification based on initial in vivo response in acute myeloid leukaemia in children without Down's syndrome: results of NOPHO-AML trials. Br J Haematol 2003; 122: 217–225.

    Article  Google Scholar 

  25. Gibson BE, Wheatley K, Hann IM, Stevens RF, Webb D, Hills RK et al. Treatment strategy and long-term results in paediatric patients treated in consecutive UK AML trials. Leukemia 2005; 19: 2130–2138.

    Article  CAS  Google Scholar 

  26. Tsukimoto I, Tawa A, Horibe K, Tabuchi K, Kigasawa H, Tsuchida M et al. Risk-stratified therapy and the intensive use of cytarabine improves the outcome in childhood acute myeloid leukemia: the AML99 trial from the Japanese Childhood AML Cooperative Study Group. J Clin Oncol 2009; 27: 4007–4013.

    Article  CAS  Google Scholar 

  27. Walter RB, Gooley TA, Wood BL, Milano F, Fang M, Sorror ML et al. Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemia. J Clin Oncol 2011; 29: 1190–1197.

    Article  Google Scholar 

  28. Bartelink IH, Bredius RG, Ververs TT, Raphael MF, van Kesteren C, Bierings M et al. Once-daily intravenous busulfan with therapeutic drug monitoring compared to conventional oral busulfan improves survival and engraftment in children undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2008; 14: 88–98.

    Article  CAS  Google Scholar 

  29. Copelan EA, Hamilton BK, Avalos B, Ahn KW, Bolwell BJ, Zhu X et al. Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood 2013; 122: 3863–3870.

    Article  CAS  Google Scholar 

  30. Sobecks RM, Rybicki L, Yurch M, Kalaycio M, Dean R, Andresen S et al. Intravenous compared with oral busulfan as preparation for allogeneic hematopoietic progenitor cell transplantation for AML and MDS. Bone Marrow Transplant 2012; 47: 633–638.

    Article  CAS  Google Scholar 

  31. Weaver CH, Clift RA, Deeg HJ, Storb R, Appelbaum FR, Bensinger W et al. Effect of graft-versus-host disease prophylaxis on relapse in patients transplanted for acute myeloid leukemia. Bone Marrow Transplant 1994; 14: 885–893.

    CAS  PubMed  Google Scholar 

  32. Bernard F, Auquier P, Herrmann I, Contet A, Poiree M, Demeocq F et al. Health status of childhood leukemia survivors who received hematopoietic cell transplantation after BU or TBI: an LEA study. Bone Marrow Transplant 2014; 49: 709–716.

    Article  CAS  Google Scholar 

  33. Loken MR, Alonzo TA, Pardo L, Gerbing RB, Raimondi SC, Hirsch BA et al. Residual disease detected by multidimensional flow cytometry signifies high relapse risk in patients with de novo acute myeloid leukemia: a report from Children's Oncology Group. Blood 2012; 120: 1581–1588.

    Article  Google Scholar 

Download references

Acknowledgements

We thank data managers from URCEST. The French childhood acute myeloid leukemia program is supported by the French national cancer institute (INCA) and the French program of clinical research (PHRC).

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Correspondence to G Michel.

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Alloin, AL., Leverger, G., Dalle, JH. et al. Cytogenetics and outcome of allogeneic transplantation in first remission of acute myeloid leukemia: the French pediatric experience. Bone Marrow Transplant 52, 516–521 (2017). https://doi.org/10.1038/bmt.2016.293

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