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Minimal Residual Disease in Peripheral Blood at Day 15 Identifies a Subgroup of Childhood B-Cell Precursor Acute Lymphoblastic Leukemia with Superior Prognosis

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Minimal Residual Disease in Peripheral Blood at Day 15 Identifies a Subgroup of Childhood B-Cell Precursor Acute Lymphoblastic Leukemia with Superior Prognosis Original Articles Minimal residual disease in peripheral blood at day 15 identifies a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with superior prognosis Jana Volejnikova, 1 Ester Mejstrikova, 1 Tatana Valova, 1 Leona Reznickova, 1 Ladislava Hodonska, 1 Vladimir Mihal, 2 Jaroslav Sterba, 3 Yahia Jabali, 4 Daniela Prochazkova, 5 Bohumir Blazek, 6 Jiri Hak, 7 Zdenka Cerna, 8 Ondrej Hrusak, 1 Jan Stary, 1 Jan Trka, 1 and Eva Fronkova 1 1Department of Pediatric Hematology and Oncology, 2 nd Faculty of Medicine, Charles University and University Hospital Motol, Prague; CLIP - Childhood Leukemia Investigation Prague; 2Department of Pediatrics, Palacky University and University Hospital Olomouc; 3Department of Pediatric Oncology, Masaryk University and University Hospital Brno; 4Department of Pediatrics, Regional Hospital Ceske Budejovice; 5Department of Pediatrics, Masaryk Hospital Usti nad Labem; 6Department of Pediatrics, University Hospital Ostrava; 7Department of Pediatrics, University Hospital Hradec Kralove, and 8Department of Pediatrics, University Hospital Plzen, Czech Republic ABSTRACT Funding: this work was supported by grants from the Czech Ministry of Education, Youth and Sports Background (MSM 0021620813), Czech Most minimal residual disease-directed treatment interventions in current treatment protocols Ministry of Health (IGA NS10472- for acute lymphoblastic leukemia are based on bone marrow testing, which is a consequence 3), Czech Science Foundation of previous studies showing the superiority of bone marrow over peripheral blood as an inves - (310/09/P058) and GAUK tigational material. Those studies typically did not explore the prognostic impact of peripheral 437911. blood involvement and lacked samples from very early time points of induction. Manuscript received on Design and Methods March 9, 2011. Revised version arrived on July 19, In this study, we employed real-time quantitative polymerase chain reaction analysis to exam - 2011. Manuscript accepted ine minimal residual disease in 398 pairs of blood and bone marrow follow-up samples taken on August 24, 2011. from 95 children with B-cell precursor acute lymphoblastic leukemia treated with the ALL IC- BFM 2002 protocol. Correspondence: Eva Fronkova, Department of Results Pediatric Hematology and We confirmed the previously published poor correlation between minimal residual disease in Oncology, Charles University, blood and marrow at early treatment time points, with levels in bone marrow being higher 2nd Faculty of Medicine, V Uvalu than in blood in most samples (median 7.9-fold, range 0.04-8,293-fold). A greater involvement 84, 150 06 Prague, Czech of peripheral blood at diagnosis was associated with a higher white blood cell count at diagno - Republic. E-mail: sis ( P=0.003) and with enlargement of the spleen ( P=0.0004) and liver ( P=0.05). At day 15, a [email protected] level of minimal residual disease in blood lower than 10 -4 was associated with an excellent 5- year relapse-free survival in 78 investigated patients (100% versus 69±7%; P=0.0003). The online version of this article -2 has a Supplementary Appendix. Subgroups defined by the level of minimal residual disease in blood at day 15 (high-risk: ≥10 , intermediate-risk: <10 -2 and ≥10 -4 , standard-risk: <10 -4 ) partially correlated with bone marrow- based stratification described previously, but the risk groups did not match completely. No other time point analyses were predictive of outcome in peripheral blood, except for a weak association at day 8. Conclusions Minimal residual disease in peripheral blood at day 15 identified a large group of patients with an excellent prognosis and added prognostic information to the risk stratification based on min - imal residual disease at day 33 and week 12. Key words: acute lymphoblastic leukemia, peripheral blood, minimal residual disease, day 15, childhood. Citation: Volejnikova J, Mejstrikova E, Valova T, Reznickova L, Hodonska L, Mihal V, Sterba J, Jabali Y, Prochazkova D, Blazek B, Hak J, Cerna Z, Hrusak O, Stary J, Trka J, and Fronkova E. Minimal residual disease in peripheral blood at day 15 identifies a subgroup of childhood B-cell pre - cursor acute lymphoblastic leukemia with superior prognosis. Haematologica 2011;96(12):1815- 1821. doi:10.3324/haematol.2011.042937 ©2011 Ferrata Storti Foundation. This is an open-access paper. haematologica | 2011; 96(12) 1815 J. Volejnikova et al. Introduction (n=6), and at the end of maintenance therapy (n=38). The median follow-up period of the study group was 6.3 years. The research Minimal residual disease (MRD) testing demonstrated was approved by the relevant institutional ethics committee. All great prognostic impact in childhood acute lymphoblastic patients or their parents or guardians gave informed consent to par - leukemia (ALL) as early as a decade ago. 1-3 Since then, it has ticipation in the study. The bone marrow MRD data from this been used in risk stratification for most progressive child - cohort, but not their impact on relapse-free survival, were pub - hood and adult ALL treatment protocols. 4-8 lished as a part of a previous study exploring the relationship Bone marrow aspirates are consistently used for MRD between bone marrow MRD and other risk factors. 15 Enlargement evaluation based on both the bone marrow location of the of the spleen and liver was evaluated by manual palpation during a disease and previous reports exploring the level of MRD in neutral respiratory phase and the results are reported in centimeters the peripheral blood compared to that in the bone marrow. below the costal margin in the mid-clavicular line. Several studies have proven that the levels of MRD in peripheral blood and bone marrow correlate well in T-ALL, Flow cytometry but that the correlation is weak in B-cell precursor ALL, Flow cytometry immunophenotyping of bone marrow aspirates with a generally lower peripheral blood MRD. 9-13 was performed at diagnosis using a recommended panel of mono - Surprisingly, only a few reports have explored the prog - clonal antibodies as described previously. 16 nostic impact of MRD in peripheral blood, although sam - pling peripheral blood is far more comfortable for patients DNA index and easier for clinicians than aspirating bone marrow. Brisco The DNA index was assessed routinely at diagnosis using the et al. 14 investigated whether peripheral blood MRD could be CycleTestPlus DNA Reagent kit (BD, San José, CA, USA) as previ - used for the early detection of bone marrow relapse and ously described. 17,18 The DNA index was defined as a ratio of the showed that MRD was detectable in the peripheral blood mode of fluorescence of cells in the G0/G1 phase and the mode of from all eight patients examined at least 10 weeks prior to fluorescence of normal peripheral blood in the G0/G1 phase. bone marrow relapse. Coustan-Smith et al. 10 showed, in a Specimens with a DNA index between 1.16 and 1.6, inclusive, limited number of patients, that patients with detectable were labeled as hyperdiploid in this study. MRD in both the peripheral blood and bone marrow at the end of induction therapy (day 46) had a significantly higher Ikaros gene deletions incidence of relapse than patients with MRD in the bone The presence of IKZF1 gene deletions was assessed by multiplex marrow only. ligation-dependent probe amplification according to the manufac - In this study, we investigated the prognostic impact of turer’s instructions (MRC Holland, kit P335). The results were eval - peripheral blood involvement at early time points of child - uated using Coffalyser v9.4 software. hood ALL treatment using the Berlin-Frankfurt-Münster (BFM) ALL IC-BFM 2002 protocol. Minimal residual disease monitoring The isolation of mononuclear cells from the diagnostic and fol - Design and Methods low-up bone marrow and peripheral blood samples; the isolation of genomic DNA; the detection of Ig heavy chain ( IGH ), Ig light Patients chain kappa ( IGK ), TCR gamma ( TCRG ), and TCR delta ( TCRD ) Ninety-five children (aged 1 to 18 years) who were newly diag - gene rearrangements by PCR amplification; heteroduplex analysis; nosed with B-cell precursor ALL between November 2002 and and sequencing were performed as described previously. 15,19-21 The April 2006 were included in this study. All children were treated in design of the patient-specific real-time quantitative PCR (RQ-PCR) the Czech Republic according to the ALL IC-BFM 2002 protocol. systems and the immunoglobulin ( IG )/ T-cell receptor ( TCR ) gene- The treatment and risk group stratification in this protocol (not based RQ-PCR MRD measurements were also described previous - based on MRD) have already been published. 15 In brief, age, white ly. 15,22-25 In all patients, at least one monoclonal IG or TCR gene blood cell count at diagnosis, response to prednisone after the first rearrangement was found. Consistent with a current BFM strategy week of therapy (“prednisone response”), and bone marrow mor - for IG/TCR -based MRD monitoring in the frontline protocol, 8 we phology at day 15 (e.g., M1-M3) were used for stratification. The regarded one patient-specific RQ-PCR assay with a minimal sensi - MRD response in the bone marrow at days 8, 15, and 33, and at tivity of 10 -4 as sufficient. We also previously showed a very good week 12 was evaluated within the accompanying scientific project correlation between values measured using two independent aimed at comparing the ALL-IC stratification with the MRD-based IG/TCR targets during ALL IC induction treatment. 26 MRD levels stratification used in the parallel AIEOP-BFM ALL 2000 study. 4,15 Of were adjusted to the percentage of leukemic blasts in the bone the 95 patients included in the current study, 45 were stratified into marrow at diagnosis. The European Study Group on Minimal the standard-risk group, 46 into the intermediate-risk group, and 4 Residual Disease in ALL (ESG-MRD-ALL) criteria for RQ-PCR sen - into the high-risk group.
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