Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors. A Children’s Oncology Group Study

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
Blood (Impact Factor: 10.45). 07/2008; 111(12):5477-85. DOI: 10.1182/blood-2008-01-132837
Source: PubMed


Minimal residual disease (MRD) is an important predictor of relapse in acute lymphoblastic leukemia (ALL), but its relationship to other prognostic variables has not been fully assessed. The Children's Oncology Group studied the prognostic impact of MRD measured by flow cytometry in the peripheral blood at day 8, and in end-induction (day 29) and end-consolidation marrows in 2143 children with precursor B-cell ALL (B-ALL). The presence of MRD in day-8 blood and day-29 marrow MRD was associated with shorter event-free survival (EFS) in all risk groups; even patients with 0.01% to 0.1% day-29 MRD had poor outcome compared with patients negative for MRD patients (59% +/- 5% vs 88% +/- 1% 5-year EFS). Presence of good prognostic markers TEL-AML1 or trisomies of chromosomes 4 and 10 still provided additional prognostic information, but not in National Cancer Institute high-risk (NCI HR) patients who were MRD(+). The few patients with detectable MRD at end of consolidation fared especially poorly, with only a 43% plus or minus 7% 5-year EFS. Day-29 marrow MRD was the most important prognostic variable in multi-variate analysis. The 12% of patients with all favorable risk factors, including NCI risk group, genetics, and absence of days 8 and 29 MRD, had a 97% plus or minus 1% 5-year EFS with nonintensive therapy. These studies are registered at as NCT00005585, NCT00005596, and NCT00005603.

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Article: Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors. A Children’s Oncology Group Study

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    • "In frontline ALL trials, risk stratification has evolved from looking at prognostic factors at diagnosis to markers of treatment response in vivo, based on evidence that minimal residual disease (MRD) is a poor prognostic factor (Borowitz et al, 2008; Marshall et al, 2013; Sutton et al, 2009; van Dongen et al, 1998). Consequently, patients with high MRD after initial therapy have been given HSCT in first remission in several ALL trials (Flohr et al, 2008; Bruggemann et al, 2010; Marshall et al, 2013). "
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    ABSTRACT: Minimal residual disease (MRD) during early chemotherapy is a powerful predictor of relapse in acute lymphoblastic leukaemia (ALL) and is used in children to determine eligibility for allogeneic haematopoietic stem cell transplantation (HSCT) in first (CR1) or later complete remission (CR2/CR3). Variables affecting HSCT outcome were analysed in 81 children from the ANZCHOG ALL8 trial. The major cause of treatment failure was relapse, with a cumulative incidence of relapse at 5 years (CIR) of 32% and treatment-related mortality of 8%. Leukaemia-free survival (LFS) and overall survival (OS) were similar for HSCT in CR1 (LFS 62%, OS 83%, n = 41) or CR2/CR3 (LFS 60%, OS 72%, n = 40). Patients achieving bone marrow MRD negativity pre-HSCT had better outcomes (LFS 83%, OS 92%) than those with persistent MRD pre-HSCT (LFS 41%, OS 64%, P < 0·0001) or post-HSCT (LFS 35%, OS 55%, P < 0·0001). Patients with B-other ALL had more relapses (CIR 50%, LFS 41%) than T-ALL and the main precursor-B subtypes including BCR-ABL1, KMT2A (MLL), ETV6-RUNX1 (TEL-AML1) and hyperdiploidy >50. A Cox multivariate regression model for LFS retained both B-other ALL subtype (hazard ratio 4·1, P = 0·0062) and MRD persistence post-HSCT (hazard ratio 3·9, P = 0·0070) as independent adverse prognostic variables. Persistent MRD could be used to direct post-HSCT therapy.
    British Journal of Haematology 10/2014; 168(3). DOI:10.1111/bjh.13142 · 4.71 Impact Factor
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    • "Moreover, they also showed a strong relationship between day 33 platelet count and MRD measurement that 74% of MRD high-risk patients had low platelet counts and authors proposed this parameter as a surrogate marker of MRD for countries with financial burdens and in situations where MRD cannot be not assessed. Despite these promising results, MRDbased risk stratification remains to be superior to all other clinically relevant risk factors and MRD negativity at the end of induction was found to be the strongest predictor of excellent outcome [16] [17]. "
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    Leukemia research 06/2014; 38(6). DOI:10.1016/j.leukres.2014.03.016 · 2.35 Impact Factor
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    • "Minimal residual disease has emerged as perhaps the most important prognostic factor in the majority of both pediatric (34, 35) and adult (36) ALL cases. A phase II study by Topp et al. evaluated the efficacy of blinatumomab at 15 μg/m2/day in 21 patients with MRD positive ALL (12). "
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    ABSTRACT: Leukemia is the most common childhood malignancy and acute lymphoblastic leukemia (ALL) represents the largest sub-type. Despite remarkable improvements over the last 40 years, standard therapy fails in 10-20% of newly diagnosed patients. Survival for children with relapsed ALL is poor, and the development and implementation of novel therapeutic strategies in pediatric ALL are critical to further advancements. Immunotherapeutic approaches have been central to more novel ALL therapies. However, more recent innovation in antibody engineering has improved potency and efficacy, and antibody-drug conjugates (ADCs) are an especially attractive option in severely immunocompromised patients. An even more sophisticated antibody design is that of bi-specific T-cell engaging or BiTE(®) antibodies, which directly recruit effector T cells to augment the anti-neoplastic effect. This review focuses on blinatumomab, a bi-specific anti-CD19/CD3 antibody that has shown efficacy in adult patients with precursor B-ALL and is currently being evaluated in the pediatric setting.
    Frontiers in Oncology 03/2014; 4:63. DOI:10.3389/fonc.2014.00063
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