Between May 1995 and August 2000 the Associazione Italiana di Ematologia Oncologia Pediatrica conducted the ALL-95 study for risk-directed, Berlin-Frankfurt-Muenster (BFM) -oriented therapy of childhood acute lymphoblastic leukemia, aimed at exploring treatment reduction in standard-risk patients (SR) and intensification during continuation therapy in intermediate-risk patients (IR) as randomized questions and treatment intensification in high-risk patients (HR). The prognostic value of DNA index was explored in this setting.
A total of 1,744 patients were enrolled (115, SR; 1,385, IR; and 244, HR). SR patients (DNA index >/= 1.16 and < 1.60; age, 1 to 5 years; and WBC < 20,000, non-T-immunophenotype, with no high-risk features) received a reduced induction therapy (no anthracyclines); IR patients were randomly assigned to receive or not receive vincristine and dexamethasone pulses during maintenance; HR therapy was based on a conventional BFM schedule intensified with three chemotherapy blocks followed by a double reinduction phase.
The event-free survival and overall survival probabilities at 10 years for the entire group were 72.5% (SE, 1.3) and 83.6% (SE, 0.9); 85.0% (SE, 3.4) and 95.5% (SE, 2.0) in SR, 75.1% (SE, 1.5) and 87.5% (SE, 0.9) in IR, and 51.0% (SE, 3.2) and 57.2% (SE, 3.3) in HR patients, respectively. Patients with a favorable DNA index had superior EFS in both IR (83.8% [2.7%] v 73.9% [1.7%]) and in HR (67.8% [9.4%] and 49.6% [3.5%]). Of the six patients with DNA index less than 0.8, only one remained in remission.
Favorable DNA index was associated with a better prognosis in IR and HR patients defined by presenting clinical criteria and treatment with a BFM-oriented chemotherapy.
"Altogether , in children with ALL, clinical parameters of adverse outcome are associated with increased levels of proapoptotic vs. anti-apoptotic genes in bone marrow MNCs. Ploidy has been recently recognized as a prognostic factor in ALL, with hyperdiploidy (DNA index ³ 1.16) being associated with a favorable prognosis (Aricò et al., 2008). In our analysis, BCL-2 mRNA showed a positive correlation with the DNA index, both at diagnosis and at the time of remission following induction therapy, whereas BAX expression was inversely correlated with the DNA index at remission. "
[Show abstract][Hide abstract] ABSTRACT: It has been suggested that leukemia is characterized by an impaired balance between the proliferation of blood cells and their capacity to undergo apoptosis. The aim of this study was to examine the expression of key molecules related to apoptosis (BCL-2, BAX, FAS, FAS-L) in children with acute lymphoblastic leukemia (ALL). Measurement of BCL-2 and BAX mRNA was performed by quantitative real-time PCR, and membrane expression of FAS and FAS-L was assessed by flow cytometry in bone marrow mononuclear cells, both at diagnosis and at remission following induction chemotherapy. At diagnosis, increased levels of the apoptotic BAX/BCL-2 ratio were observed in children older than 10 years and with higher white blood cell counts. A DNA index < 1.16 was associated with increased BAX/BCL-2, both at diagnosis and at remission, and the del(9p) chromosome abnormality with increased BAX/BCL-2 at remission. The expression of the apoptotic receptor FAS was significantly higher at remission compared to diagnosis, which might reflect enhanced sensitivity of the leukemic clone to apoptosis and response to treatment. Altogether, our results highlight the association of apoptosis-related genes with clinical and cytogenetic prognostic parameters in pediatric ALL. A better understanding of the mechanisms and regulation of apoptosis should enable the design of novel targeted therapies for these patients.
"Over the past few decades, the prognosis of children and adolescents with acute leukemia has greatly improved, because of advances in risk assessment, tailored chemotherapy, optimal recourse to hematopoietic stem cell transplantation and innovative supportive care . The cure rates now exceed 80% for children with acute lymphoblastic leukemia (ALL) and 50% for those with acute myeloid leukemia (AML)   . "
[Show abstract][Hide abstract] ABSTRACT: Acute leukemia is the most common type of childhood and adolescence cancer, characterized by clonal proliferation of variably differentiated myeloid or lymphoid precursors. Recent insights into the molecular pathogenesis of leukemia have shown that epigenetic modifications, such as deacetylation of histones and DNA methylation, play crucial roles in leukemogenesis, by transcriptional silencing of critical genes. Histone deacetylases (HDACs) are potential targets in the treatment of leukaemia, and, as a consequence, inhibitors of HDACs (HDIs) are being studied for therapeutic purposes. HDIs promote or enhance several different anticancer mechanisms, such as apoptosis, cell cycle arrest, and cellular differentiation and, therefore, are in evidence as promising treatment for children and adolescents with acute leukemia, in monotherapy or in association with other anticancer drugs. Here we review the main preclinical and clinical studies regarding the use of HDIs in treating childhood and adolescence leukemia.
BioMed Research International 01/2011; 2011(5-6):148046. DOI:10.1155/2011/148046 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The presenting features and treatment outcome of 120 patients with Down syndrome (DS) and childhood acute lymphoblastic leukemia (ALL) were compared with 6237 non-DS patients treated in the same years.
We reviewed the database of 6 consecutive Italian Association of Pediatric Hematology and Oncology (AIEOP)-ALL trials conducted between 1982 and 2004. Features of DS patients were compared with those of non-DS patients.
The 120 DS patients (1.9%) were more often girls (P = .027), aged > or = 10 years (P = .014), and high risk according to National Cancer Institute (NCI) criteria (P = .045). The distribution of white blood cell count did not differ (P = .32). DS patients belonged less frequently to the current high-risk group (P = .017). In all but 1 case they demonstrated B-cell precursor (BCP) immunophenotype (P < or = .001). TEL/AML1 molecular fusion transcript was found in only 1 of 44 (2.2%) tested patients. Induction death occurred more often in DS patients (4.2%, P = .009), but not failure to achieve remission. Leukemia relapse occurred in 31.6% of DS patients (vs 23.5%; P = .003), usually in the marrow. Remission death was more frequent in DS patients (4.2%, P = .03). Ten-year event-free survival and survival were significantly worse compared with non-DS patients (P < 0.001). DS patients diagnosed since 1995 had a better outcome (P = .06) than those diagnosed in previous years, but still had worse outcomes than non-DS patients (P = .04). Event-free survival of DS patients at NCI standard risk was lower than that of non-DS patients (P = .006).
Presenting features of childhood ALL in DS differ from those in non-DS patients. They are almost invariably characterized by BCP phenotype, and are often TEL/AML1 negative. Treatment results, although not as good as for non-DS patients, improved progressively, with modern therapy and support allowing 75% to survive.
Cancer 08/2008; 113(3):515-21. DOI:10.1002/cncr.23587 · 4.89 Impact Factor
S. M. F. Pluijm, M. A. den Hoed, M. M. van den Heuvel-Eibrink
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