The prognostic significance of early response to treatment has not been reported in relapsed pediatric acute myeloid leukemia. In order to identify an early and easily applicable prognostic factor allowing subsequent treatment modifications, we assessed leukemic blast counts in the bone marrow by morphology on days 15 and 28 after first reinduction in 338 patients of the international Relapsed-AML2001/01 trial. Both day 15 and day 28 status was classified as good (≤20% leukemic blasts) in 77% of patients. The correlation between day 15 and 28 blast percentages was significant, but not strong (Spearman correlation coefficient = 0.49, P<0.001). Survival probability decreased in a stepwise fashion along with rising blast counts at day 28. Patients with bone marrow blast counts at this time-point of ≤5%, 6-10%, 11-20% and >20% had 4-year probabilities of survival of 52%±3% versus 36%±10% versus 21%±9% versus 14%±4%, respectively, P<0.0001; this trend was not seen for day 15 results. Multivariate analysis showed that early treatment response at day 28 had the strongest prognostic significance, superseding even time to relapse (< or ≥12 months). In conclusion, an early response to treatment, measured on day 28, is a strong and independent prognostic factor potentially useful for treatment stratification in pediatric relapsed acute myeloid leukemia. This study was registered with ISRCTN code: 94206677.

AIEOP c o Department of Pediatrics Hospital S Gerardo Monza Italy

BFM AML Group Hannover c o Pediatric Hematology Oncology Hannover Medical High School Germany

BFM AML Group St Anna Children's Hospital and Children's Cancer Research Institute Department of Pediatrics Medical University of Vienna Austria

Center of Pediatric Hematology Oncology Schneider Children's Medical Center of Israel Petah Tikva Israel

CPH c o Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine and University Hospital Motol Charles University Prague Czech Republic

FRALLE CLCG c o Institut d'Hématologie et d'Oncologie Pédiatrique Lyon France

FRALLE CLCG; c o Unité d'Onco Hématologie Pédiatrique Hôpital d'Enfants Armand Trousseau Paris France

Hong Kong Paediatric Haematology and Oncology Study Group c o Department of Paediatrics and Adolescent Medicine Queen Mary Hospital Hong Kong China

NOPHO Department of Pediatrics Queen Silvia's Children's Hospital Göteborg Sweden

NOPHO; Department of Pediatrics Aarhus University Hospital Skejby Denmark

Pediatric Oncology Hematology Beatrix Children's Hospital UMCG Groningen The Netherlands Dutch Childhood Oncology Group The Hague The Netherlands

Pediatric Oncology Hematology VU University Medical Center Amsterdam The Netherlands Dutch Childhood Oncology Group The Hague The Netherlands

Research Center for Pediatric Hematology Oncology and Immunology Moscow Russia

St Jude's Children Research Hospital Memphis TN USA c o Children's Center For Cancer and Blood Diseases Peyton Manning Children's Hospital at St Vincent Indianapolis IN USA

UK CCLG; c o Department of Haematology and Oncology Our Lady's Children's Hospital Dublin Ireland

UK NCRI Childhood Leukaemia Group Department of Paediatric Haematology Royal Hospital for Sick Children Glasgow Scotland UK

Zobrazit více v PubMed

Goemans BF, Tamminga RY, Corbijn CM, Hahlen K, Kaspers GJ. Outcome for children with relapsed acute myeloid leukemia in the Netherlands following initial treatment between 1980 and 1998: survival after chemotherapy only? Haematologica 2008;93(9):1418–20. PubMed

Gorman MF, Ji L, Ko RH, Barnette P, Bostrom B, Hutchinson R, et al. Outcome for children treated for relapsed or refractory acute myelogenous leukemia (rAML): a Therapeutic Advances in Childhood Leukemia (TACL) Consortium study. Pediatr Blood Cancer. 2010;55(3):421–9. PubMed

Abrahamsson J, Clausen N, Gustafsson G, Hovi L, Jonmundsson G, Zeller B, et al. Improved outcome after relapse in children with acute myeloid leukaemia. Br J Haematol. 2007;136(2):229–36. PubMed

Aladjidi N, Auvrignon A, Leblanc T, Perel Y, Benard A, Bordigoni P, et al. Outcome in children with relapsed acute myeloid leukemia after initial treatment with the French Leucemie Aique Myeloide Enfant (LAME) 89/91 protocol of the French Society of Pediatric Hematology and Immunology. J Clin Oncol. 2003;21(23): 4377–85. PubMed

Rubnitz JE, Razzouk BI, Lensing S, Pounds S, Pui CH, Ribeiro RC. Prognostic factors and outcome of recurrence in childhood acute myeloid leukemia. Cancer. 2007; 109(1):157–63. PubMed

Sander A, Zimmermann M, Dworzak M, Fleischhack G, von Neuhoff C, Reinhardt D, et al. Consequent and intensified relapse therapy improved survival in pediatric AML: results of relapse treatment in 379 patients of three consecutive AML-BFM trials. Leukemia. 2010; 24(8):1422–8. PubMed

Webb DK, Wheatley K, Harrison G, Stevens RF, Hann IM. Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial. MRC Childhood Leukaemia Working Party. Leukemia. 1999;13(1):25–31. PubMed

Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, et al. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013;31(5):599–607. PubMed

Kaspers GJ. Pediatric acute myeloid leukemia. Expert Rev Anticancer Ther. 2012; 12(3):405–13. PubMed

Stahnke K, Boos J, Bender-Gotze C, Ritter J, Zimmermann M, Creutzig U. Duration of first remission predicts remission rates and long-term survival in children with relapsed acute myelogenous leukemia. Leukemia. 1998;12(10):1534–38. PubMed

Creutzig U, Zimmermann M, Ritter J, Henze G, Graf N, Loffler H, et al. Definition of a standard-risk group in children with AML. Br J Haematol. 1999; 104(3):630–9. PubMed

Langebrake C, Creutzig U, Dworzak M, Hrusak O, Mejstrikova E, Griesinger F, et al. Residual disease monitoring in childhood acute myeloid leukemia by multiparameter flow cytometry: the MRD-AML-BFM Study Group. J Clin Oncol. 2006;24(22): 3686–92. PubMed

Kern W, Haferlach T, Schoch C, Loffler H, Gassmann W, Heinecke A, et al. Early blast clearance by remission induction therapy is a major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: data from the German AML Cooperative Group (AMLCG) 1992 Trial. Blood. 2003;101(1):64–70. PubMed

Inaba H, Coustan-Smith E, Cao X, Pounds SB, Shurtleff SA, Wang KY, et al. Comparative analysis of different approaches to measure treatment response in acute myeloid leukemia. J Clin Oncol. 2012;30(29):3625–32. PubMed PMC

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(8):1581–8. PubMed PMC

Rubnitz JE, Inaba H, Dahl G, Ribeiro RC, Bowman WP, Taub J, et al. Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial. Lancet Oncol. 2010;11(6): 543–52. PubMed PMC

Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21(24):4642–9. PubMed

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(16): 3187–205. PubMed

Survival Following Relapse in Children with Acute Myeloid Leukemia: A Report from AML-BFM and COG

Second Relapse of Pediatric Patients with Acute Myeloid Leukemia: A Report on Current Treatment Strategies and Outcome of the AML-BFM Study Group

Gemtuzumab ozogamicin in children with relapsed or refractory acute myeloid leukemia: a report by Berlin-Frankfurt-Münster study group

Clofarabine, high-dose cytarabine and liposomal daunorubicin in pediatric relapsed/refractory acute myeloid leukemia: a phase IB study