Childhood acute lymphoblastic leukemia

As cure rates in childhood acute lymphoblastic leukemia reach 80%, emphasis is increasingly placed on the accurate identification of drug-resistant cases, the elucidation of the mechanisms involved in drug resistance and the development of new therapeutic strategies targeted toward the pivotal molecular lesions. Pharmacodynamic and pharmacogenomic studies have provided rational criteria for individualizing therapy to enhance efficacy and reduce acute toxicity and late sequelae. Currently, assessment of the early response to treatment by measurement of minimal residual disease (MRD) is the most powerful independent prognostic indicator. MRD is affected by both the drug sensitivity of leukemic cells and the pharmacodynamic and pharmacogenetic properties of the host cells. Rapid advances in biotechnology and bioinformatics should ultimately facilitate the development of molecular diagnostic assays that can be used to optimize antileukemic therapy and elucidate the mechanisms of leukemogenesis. In the interim, prospective clinical trials have provided valuable clues that are further increasing the cure rate of childhood acute lymphoblastic leukemia.     

Pharmacogenomics of acute lymphoblastic leukemia

Pharmacogenomics of acute lymphoblastic leukemia (ALL) evolved rapidly in the past few years. Majority of recent findings concerns knowledge on key components of ALL treatment, 6-mercaptopurine and methotrexate. Leukemia is the most common cancer affecting children, with ALL comprising 80 % of all leukemia cases. Introduction of treatment protocols composed of several chemotherapeutic agents improved importantly survival in patients with ALL. Nevertheless, ALL is still the leading cause of cancer-related death in children. Interindividual differences in drug responses are an important cause of resistance to treatment and adverse drug reactions. Identifying pharmacogenomic determinants of drugs used in ALL treatment may allow for prospective identification of patients with suboptimal drug responses allowing for complementation of traditional treatment protocols by genotype-based drug dose adjustment.     

Telomeric fusion in pre-T-cell acute lymphoblastic leukemia

Summary Telomeric fusion, a rare phenomenon, was observed in malignant cells from the peripheral blood of an 18-year-old male with rapidly progressive pre-T-cell acute lymphoblastic leukemia (ALL). Only two comparable cases, both with B-cell ALL, have been reported with telomeric fusion in neoplasia. All of the leukemic cells examined from our patient had two chromosome abnormalities consisting of partial triplication (trp) of chromosome 2 and a derivative chromosome 3. Approximately a third of the leukemic cells showed in addition telomere-telomere fusions. These involved the telomeric regions of 1p, 2p, 4q, 5q, 7q, 10q, 11q, 12p, 15p, 21p, and Xq and 3p of the derivative (3). The findings in this case suggest that telomeric fusion may function as a mechanism for the development of chromosome rearrangements that may play a role, albeit rarely, in human neoplasia.     

Mechanism of relapse in pediatric acute lymphoblastic leukemia

Relapse following initial chemotherapy remains a barrier to survival in approximately 20% of children suffering from acute lymphoblastic leukemia (ALL). Recently, to investigate the mechanism of relapse, we analysed clonal populations in 27 pairs of matched diagnosis and relapse ALL samples using PCR-based detection of multiple antigen receptor gene rearrangements. These clonal markers revealed the emergence of apparently new populations at relapse in 13 patients. In those cases where the new ‘relapse clone’ could be detected in the diagnosis population, there was a close correlation between length of first remission and quantity of the relapse clone in the diagnosis sample. A shorter length of time to first relapse correlated with a higher quantity of the relapsing clone at diagnosis. This observation, together with demonstrated differential chemosensitivity between sub-clones at diagnosis, indicates that relapse in ALL patients may commonly involve selection of a minor intrinsically resistant sub-clone that is undetectable by routine PCR-based methods. From a clinical perspective, relapse prediction may be improved with strategies to detect minor potentially resistant sub-clones early during treatment, hence allowing intensification of therapy. Together with the availability of relevant in vivo experimental models and powerful technology for detailed analysis of patient specimens, this new information will help shape future experimentation towards targeted therapy for high-risk ALL.     

Stages of B-lymphocyte differentiation in acute lymphoblastic leukemia

Blasts phenotype was determined in 61 children with the acute lymphoblastic leukemia. Non-T-cell acute lymphoblastic leukemia was diagnosed in 51 children. Stages of blasts differentiation were determined with the aid of monoclonal antibodies set using alkaline phosphatase-anti-alkaline phosphatase technique. Blasts in 50 patients belonged to B subpopulation confirmed by the presence of panB CD19 and CD22 antigens. Common antigen was seen in 76.5% of the examined patients with non-T-cell acute lymphoblastic leukemia. Cases of non-T-cell acute lymphoblastic leukemia were divided into 8 subgroups depending on the antigens of B-cells differentiation. An identification of pre-B subgroups of the acute lymphoblastic leukemia indicates heterogenicity of the acute lymphoblastic leukemias in childhood and enables their classification into groups corresponding to the early stages of lymphoblasts maturation.     

Pre-B cell receptor signaling in acute lymphoblastic leukemia

B cell lineage ALL represents by far the most frequent malignancy in children and is also common in adults. Despite significant advances over the past four decades, cytotoxic treatment strategies have recently reached a plateau with cure rates at 80 percent for children and 55 percent for adults. Relapse after cytotoxic drug treatment, initial drug-resistance and dose-limiting toxicity are among the most frequent complications of current therapy approaches. For this reason, pathway-specific treatment strategies in addition to cytotoxic drug treatment seem promising to further improve therapy options for ALL patients. In a recent study on 111 cases of pre-B cell-derived human ALL, we found that ALL cells carrying a BCR-ABL1-gene rearrangement lack expression of a functional pre-B cell receptor in virtually all cases. In a proof-of-principle experiment, we studied pre-B cell receptor function during progressive leukemic transformation of pre-B cells in BCR-ABL1-transgenic mice: Interestingly, signaling from the pre-B cell receptor and the oncogenic BCR-ABL1 kinase are mutually exclusive and only "crippled" pre-B cells that fail to express a functional pre-B cell receptor are permissive to transformation by BCR-ABL1.     

Epigenetic analysis of childhood acute lymphoblastic leukemia

We used a chromosome 3 wide NotI microarray for identification of epigenetically inactivated genes in childhood acute lymphoblastic leukemia (ALL). Three novel genes demonstrated frequent methylation in childhood ALL. PPP2R3A (protein phosphatase 2, regulatory subunit B'', alpha) was frequently methylated in T (69%) and B (82%)-ALL. Whilst FBLN2 (fibulin 2) and THRB (thyroid hormone receptor, beta) showed frequent methylation in B-ALL (58%; 56% respectively), but were less frequently methylated in T-ALL (17% for both genes). Recently it was demonstrated that BNC1 (Basonuclin 1) and MXS1 (msh homeobox 1) were frequently methylated across common epithelial cancers. In our series of childhood ALL BNC1 was frequently methylated in both T (77%) and B-ALL (79%), whilst MSX1 showed T-ALL (25%) specific methylation. The methylation of the above 5 genes was cancer specific and expression of the genes could be restored in methylated leukemia cell lines treated with 5-aza-2’-deoxycytidine. This is the first report demonstrating frequent epigenetic inactivation of PPP2R3A, FBLN2, THRB, BNC1 and MSX1 in leukemia. The identification of frequently methylated genes showing cancer specific methylation will be useful in developing early cancer detection screens and for targeted epigenetic therapies.     

Quantitative expression of TEL in childhood acute lymphoblastic leukemia

Loss of heterozygosity of chromosome 12p in human precursor B-cell ALL invariably results in loss of TEL coding sequences. Accompanied by a 12;21 translocation, such loss of heterozygosity ensures complete loss of the wild-type TEL. No inactivating mutations of the retained TEL allele have been reported in leukemias with hemizygous deletion. However, only minimal data reported the expression of the wild-type TEL in ALL. We now demonstrate that quantitative real-time RT-PCR from leukemic RNA samples could be indicative of compromised TEL expression in childhood ALL and therefore loss of TEL function.     

Lipid and lipoprotein abnormalities in acute lymphoblastic leukemia survivors

Survivors of acute lymphoblastic leukemia (ALL), the most common cancer in children, are at increased risk of developing late cardiometabolic conditions. However, the mechanisms are not fully understood. This study aimed to characterize the plasma lipid profile, Apo distribution, and lipoprotein composition of 80 childhood ALL survivors compared with 22 healthy controls. Our results show that, despite their young age, 50% of the ALL survivors displayed dyslipidemia, characterized by increased plasma triglyceride (TG) and LDL-cholesterol, as well as decreased HDL-cholesterol. ALL survivors exhibited lower plasma Apo A-I and higher Apo B-100 and C-II levels, along with elevated Apo C-II/C-III and B-100/A-I ratios. VLDL fractions of dyslipidemic ALL survivors contained more TG, free cholesterol, and phospholipid moieties, but less protein. Differences in Apo content were found between ALL survivors and controls for all lipoprotein fractions except HDL₃. HDL₂, especially, showed reduced Apo A-I and raised Apo A-II, leading to a depressed Apo A-I/A-II ratio. Analysis of VLDL-Apo Cs disclosed a trend for higher Apo C-III₁ content in dyslipidemic ALL survivors. In conclusion, this thorough investigation demonstrates a high prevalence of dyslipidemia in ALL survivors, while highlighting significant abnormalities in their plasma lipid profile and lipoprotein composition. Special attention must, therefore, be paid to these subjects given the atherosclerotic potency of lipid and lipoprotein disorders.     

Combination chemotherapy for acute lymphoblastic leukaemia in adults.

Fifty-one adults with acute lymphoblastic leukaemia were entered into a trial of intense initial chemotherapy and early "prophylaxis" of the central nervous system (CNS). Initial treatment with OPAL (Oncovin (vincristine), prednisolone, adriamycin (doxorubicin), and L-asparaginase (colaspase)) followed by craniospinal or cranial irradiation and intrathecal methotrexate produced remission in 36 patients (71%). Seventeen of these patients relapsed three to 18 months after the start of remission; the remainder had been in remission for 12 to 52 months by the end of the study. The predicted median duration of complete remission was 18.5 months. None of the four patients who initially had clinical evidence of CNS disease, three of whom also had leukaemic cells identical to those found in Burkitt''s lymphoma, achieved remission. Those patients who initially had hepatomegaly or splenomegaly had a shorter remission than those without. The predicted median survival was 27 months in those who achieved complete remission, one month in those who did not, and 21 months overall. The addition of colaspase and doxorubicin to vincristine and prednisolone and the use of early CNS treatment clearly improved the remission rate among adults with acute lymphoblastic leukaemia, though the presence and length of remission was affected by the extent of disease at presentation. Burkitt-like leukaemia, which had a poor prognosis, is probably a separate disease and may benefit from a different therapeutic approach.     

Cytogenetics and molecular genetics of acute lymphoblastic leukemia

An important factor in the diagnosis of acute lymphoblastic leukemia (ALL) is that karyotype is an independent prognostic indicator, with an impact on the choice of treatment. Outcome is related to the number of chromosomes. For example, high hyperdiploidy (51-65 chromosomes) is associated with a good prognosis, whereas patients with near haploidy (23-29 chromosomes) have a poor outcome. The discovery of recurring chromosomal abnormalities in the leukemic blasts of patients with ALL has identified a large number of genes involved in leukemogenesis. Certain specific genetic changes are related to prognosis. The ETV6/AML1 fusion arising from the translocation (t12;21) (p13;q22) has been associated with a good outcome; the BCR/ABL fusion of (t9;22)(q34;q11), rearrangements of the MLL gene, and abnormalities of the short arm of chromosomes 9 involving the tumor suppressor genes p16INK4A have a poor prognosis. Unfortunately, the classification of patients into prognostic groups based on cytogenetics is not always as predicted. Even when other clinically based risk factors are taken into account, some patients with good-risk cytogenetic features will relapse. In the search for new measures of prognosis, it has recently emerged that the level of minimal residual disease following induction therapy can be a reliable predictor of outcome in ALL.     

Comparative treatment of acute leukemia in adults

13 full remissions and 8 partial remissions were achieved in 32 first treatments of acute leukaemia. The average duration of full remissions amounted to 225 days, that of partial remissions was 140 days. The average survival time of responders amounted to 410 days, that of non-responders was 52 days. The results of 18 recidive treatments were distinctly worse. Allowing for alexane permanent infusion, the findings and complications of different therapeutical schemes were compared. Improvements of the results seem to be only possible, if cytostatic treatment is supplemented by taking initial and progress evaluating, prognostic relevant parameters into consideration (e.g. stem cell cultures), and by escalating supportive measures including histocompatible blood cell substitution and reverse isolation as well as transplantation of human bone-marrow.