Monitoring treatment response of childhood precursor B-cell acute lymphoblastic leukemia in the AIEOP-BFM-ALL 2000 protocol with multiparameter flow cytometry: predictive impact of early blast reduction on the remission status after induction

Treatment response is a strong outcome predictor for childhood acute lymphoblastic leukemia (ALL). Here, we evaluated the predictive impact of flow cytometric blast quantification assays (absolute blast count, BC, and blast reduction rate, BRR) in peripheral blood (pB) and/or bone marrow (BM) at early time points of induction therapy (days 0, 8 and 15) on the remission status in the AIEOP-BFM-ALL 2000 protocol. At the single parameter level (905 patients), the strongest predictive parameter for the remission status as a dichotomous minimal residual disease (MRD) parameter (positive/negative) has been provided by the BC at day 15 in BM (cutoff: 17 blasts/μl; 50 vs 15%; odds ratio: 5.6; 95% confidence interval: 4.1–7.6, P<0.001), followed by the BRR at day 15 in BM and by the BC at day 8 in pB (odds ratios: 3.8 and 2.6, respectively). In the multiple regression analysis (440 patients), BC in pB (d0 and d8) and in BM (d15) as well as BRR at day 8 in pB provided significantly contributing variables with an overall correct prediction rate of 74.8%. These data show that the quantitative assessment of early response parameters, especially absolute BCs at day 15 in BM, has a predictive impact on the remission status after induction therapy.

[1]  M. Zweig,et al.  Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. , 1993, Clinical chemistry.

[2]  W. Hiddemann,et al.  Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. , 2000, Blood.

[3]  A. Biondi,et al.  Molecular monitoring of childhood acute lymphoblastic leukemia using antigen receptor gene rearrangements and quantitative polymerase chain reaction technology. , 2005, Haematologica.

[4]  P. Greenland,et al.  Selection and interpretation of diagnostic tests and procedures. Principles and applications. , 1981, Annals of internal medicine.

[5]  Giuseppe Basso,et al.  Standardization of flow cytometric minimal residual disease evaluation in acute lymphoblastic leukemia: Multicentric assessment is feasible , 2008, Cytometry. Part B, Clinical cytometry.

[6]  G. Bonney,et al.  Logistic regression for dependent binary observations. , 1987, Biometrics.

[7]  J. V. van Dongen,et al.  Molecular monitoring of residual disease using antigen receptor genes in childhood acute lymphoblastic leukaemia. , 2002, Best practice & research. Clinical haematology.

[8]  H. Sather,et al.  Cytoreduction and prognosis in acute lymphoblastic leukemia--the importance of early marrow response: report from the Childrens Cancer Group. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  Eugene Demidenko,et al.  Sample size and optimal design for logistic regression with binary interaction , 2008, Statistics in medicine.

[10]  C. Pratt,et al.  St. Jude Children's Research Hospital. , 1997, Pediatric hematology and oncology.

[11]  M. Schrappe.  Prognostic factors in childhood acute lymphoblastic leukemia , 2003, Indian journal of pediatrics.

[12]  F. Berthold,et al.  [Corticosteroid-dependent reduction of leukocyte count in blood as a prognostic factor in acute lymphoblastic leukemia in childhood (therapy study ALL-BFM 83)]. , 1987, Klinische Padiatrie.

[13]  B. Schäfer,et al.  Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia , 2008, Leukemia.

[14]  F. Behm,et al.  Long-term results of Total Therapy studies 11, 12 and 13A for childhood acute lymphoblastic leukemia at St Jude Children's Research Hospital , 2000, Leukemia.

[15]  C. Pui,et al.  The eighth international childhood acute lymphoblastic leukemia workshop (‘Ponte di Legno meeting’) report: Vienna, Austria, April 27–28, 2005 , 2006, Leukemia.

[16]  J. Shuster,et al.  Long-term results of treatment studies for childhood acute lymphoblastic leukemia: Pediatric Oncology Group studies from 1986–1994 , 2000, Leukemia.

[17]  J. Harbott,et al.  Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Münster. , 2000, Leukemia.

[18]  Frederick E. Petry,et al.  Principles and Applications , 1997 .

[19]  H. Sather,et al.  Early response to therapy and outcome in childhood acute lymphoblastic leukemia , 1997, Cancer.

[20]  J. Harbott,et al.  Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995 , 2000, Leukemia.

[21]  S. Hunger,et al.  Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study. , 2008, Blood.

[22]  J. Ritter,et al.  Die Corticosteroid-abhängige Dezimierung der Leukämiezellzahl im Blut als Prognosefaktor bei der akuten lymphoblastischen Leukämie im Kindesalter (Therapiestudie ALL-BFM 83) , 1987 .

[23]  Michael N Dworzak,et al.  Prognostic significance and modalities of flow cytometric minimal residual disease detection in childhood acute lymphoblastic leukemia. , 2002, Blood.

[24]  F. Behm,et al.  Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. , 2002, Blood.

[25]  A. Berg,et al.  Long-term follow-up of Dutch Childhood Leukemia Study Group (DCLSG) protocols for children with acute lymphoblastic leukemia, 1984–1991 , 2000, Leukemia.