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Abstract
Acute lymphoblastic leukaemia, the malignant disorder of lymphoid progenitor cells, affects both children and adults, with peak prevalence between the ages of 2 and 5 years. Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in patients younger than 15 years, accounting for 23 % of all cancers and 76 % of all leukemias in this age group.
Advances in our understanding of the pathobiology of acute lymphoblastic leukaemia, fuelled by emerging molecular and cytogenetic technologies, suggest that targeting the genetic defects of leukemic cells could revolutionise management of this disease.
Genetic alterations, as detected by conventional cytogenetics and/or molecular analysis, have been shown to identify biologically and clinically significant disease subtypes in ALL. The karyotypes of leukemic cells not only have diagnostic and prognostic importance, but also indicate sites of molecular lesions potentially involved in cell transformation and proliferation. However, this process is time consuming, highly dependent upon operator experience and may miss near-haploid or tetraploid leukemia lines.
Assessment of the DNA content of leukemic cells by flow cytometry (DNA index) is a useful adjunct to conventional cytogenetic ploidy analysis because it is automated, rapid, not affected by the mitotic index of the cell population and detects near-haploid or tetraploid leukemia lines that were missed by routine karyotyping.
The aim of the present work was to study the DNA index in blast cells in peripheral blood in childhood acute lymphoblastic leukemia at initial diagnosis to detect the ploidy status of blast cells and delineate its relation to clinical and laboratory prognostic criteria as well as response to induction therapy.
The present study was conducted on thirty children with newly diagnosed acute lymphoblastic leukemia. The patients were admitted to Hematology / Oncology Unit of the Alexandria Children’s Hospital during the period from February 2006 through February 2007.they were 15 males and 15 females. Their ages ranged between 2.5 and 12 years.
They were further subdivided into two groups according to National Cancer Institute (NCI) risk classification criteria for childhood ALL. Standard risk group (16 children) ; with age at diagnosis 1 to 9 years and with initial white blood cell count less than 50.000/mm3.High risk group (14 children); with age at diagnosis outside the limit of 1 to 9 years and/or initial white blood cell count more than 50.000/mm3
All patients included in this study were subjected to: thorough history taking, complete physical examination including: general examination, assessment the size of liver and spleen and for detection of any abdominal masses and organ involvement, chest examination and other presentations as CNS disease at diagnosis, skin involvement. .Hematological investigation included: CBC at diagnosis and at day 7 and day 14 , bone marrow examination at diagnosis on day 14 and day 28 of induction. In addition CSF examination for blast cells , routine biochemical investigations (serum creatinine level, blood urea nitrogen, ALT, AST and serum uric acid), chest X-ray and abdominal ultrasonography . Immunophenotyping (to confirm B or T linage in ALL cases) using the following panel: CD2 , CD3 , CD5 , CD7 , CD10 , CD13 , CD14 ,CD19 , CD33 ,CD34 , Cyt Igm and HLA-DR. Specific measurement of DNA index by flowcytometry on peripheral blood blast cells at time of diagnosis using DNA cycle test. These data were statistically analyzed.
The results of the present study revealed that patients included in the high risk group had a constellation of clinical and hematological criteria indicative of high tumor burden, a less favorable initial treatment response as monitored by CBC d7 & BM d14 and a worse overall treatment outcome.
Studying the DNA index of blast cells in both groups showed significant statistical difference at time of diagnosis with favorable higher hyperdiploidy in standard risk group. Meaning that lowering of DNA index was associated with high risk ALL.
DNA index > 1.6 (near triploidy and near tetraploidy) was found in 27% of our cases. All of them achieved successful induction of remission except only one (a male child with T-ALL).
DNA index ranging from 1.16-1.6 was found in 30% of our cases. All cases achieved successful remission; except two (high risk group and died during induction of remission). This finding states that hyperdiploidy state with DNA index 1.16-1.6 is usually associated with better prognosis.
DNA index ranging from 0.85-1.15 was detected in 23% of our cases. All achieved induction of remission i.e. good prognosis except one case.
These findings can be explained by the fact that the hyperdiploid leukemic cells are particularly susceptible to apoptosis and accumulate methotrexate and its metabolites.
On the other hand; hypodiploid state (DNA index < 0. 85) was detected in 20% of our cases.. They were associated with bad prognosis as half of them failed to achieve induction of remission.
In a trial to find a correlation between DNA index and other prognostic variables, there was significant positive correlation between the DNA index and B.M. blasts % (at diagnosis),but no correlations were found between DNA index and other prognostic variables.