Table of contents :

  • Epidemiology
  • Aetiology
  • Pathogenesis
  • Symptoms & signs
  • Laboratory examinations
  • Differential diagnosis
  • Therapy
  • Prognosis
  • Web resources

  • Epidemiology : it is more common in males than in females and affects children and adults equally; 20% of all ALLs; 10%-15% of pediatric and 25% of adult ALL cases; L1 or L2
    Pathogenesis : translocations involving

    ... are compatible with illegitimate V(D)J recombination between a TcR locus and a proto-oncogene locus bearing a fortuitous but functional recombination site. Transcription factors are known to be deregulated by chromosomal translocations, but mutations in protein tyrosine kinases have only rarely been identified. The extrachromosomal (episomal) amplification of ABL1, an aberration that is not detectable by conventional cytogenetics, occurs in 5.6% of individuals with T-ALL. Molecular analyses delineated the amplicon as a 500-kb region from chromosome band 9q34, containing the fusion between oncogenes ABL1 and NUP214. The constitutively phosphorylated tyrosine kinase NUP214-ABL1 is sensitive to the tyrosine kinase inhibitor imatinib. The recurrent cryptic NUP214-ABL1 rearrangement is associated with increased HOX expression and deletion of CDKN2A 9, consistent with a multistep pathogenesis of T-ALLref. g
    In 1991, Ellisen et alref identified TAN-1 (translocation-associated NOTCH), a gene fused to the TCRb locus by a t(7;9)(q34;q34.3) in T-ALL. Notch was the gene product responsible for the notched wing phenotype in Drosophila and had been demonstrated to play a major role in cell fate determination of the fly nervous systemref. Subsequent functional studies showed that the very rare T-ALLs with a t(7;9) expressed a truncated, activated form of TAN-1 (now termed NOTCH1) with leukemogenic propertiesref. Notch1 was also demonstrated to be involved in regulation of thymocyte differentiation, and was essential for normal T-cell developmentref. Biologic studies showed that NOTCH1 encodes a transmembrane receptor that undergoes a series of proteolytic cleavage steps, the last of which is catalyzed by g-secretase to produce intracellular Notch1 (ICN) protein that is involved in transcriptional regulationref. In 2004, Weng et al reported that > 50% of human T-ALLs, including tumors from all major molecular oncogenic subtypes, have activating mutations that involve the extracellular heterodimerization domain and/or the C-terminal PEST domain of NOTCH1, suggesting that Notch might be a rational therapeutic targetref. Potential agents were already available because g-secretase plays an important role in cleavage of amyloid precursor protein to amyloid b-peptide, a major constituent of amyloid plaques in Alzheimer disease. g-secretase inhibitors (GSIs) blocked transcriptional activation induced by mutated Notch1 polypeptides similar to those present in T-ALLref. Taken together, these data created great interest in the use of GSIs in T-ALL, and phase 1 clinical trials were initiated. At the same time, other studies began to examine whether NOTCH1 mutations had prognostic significance. Leukemia cells from 52% of T-ALL patients enrolled in the ALL-BFM 2000 trial had NOTCH1 mutations, while no mutations were present in 50 B-precursor ALL controls. Most clinical characteristics were no different in those with/without NOTCH1 mutations, but there was a strong association between the presence of NOTCH1 mutations and an excellent early response to therapy, measured either by response to the 7-day prednisone prophase or levels of minimal residual disease (MRD) present at the end of induction or consolidation therapy. Furthermore, patients with NOTCH1 mutations had a significantly better event-free survival (EFS) than those without mutations (90% vs 71% at 4 years), due to a 4-fold higher risk of relapse among the NOTCH1 germ-line patients. NOTCH1 mutation status may turn out to be a critical prognostic factor in T-ALL that can help differentiate between patients at high versus low risk of relapse. These results also raise the question of how molecularly targeted therapy can be integrated into therapeutic strategies for patients with an excellent expected treatment outcome. It is relatively straightforward to design a trial of targeted therapy in patients expected to have a poor outcome: one applies the experimental therapy and assesses response, either in terms of complete remission rate or perhaps by log-reduction in MRD. How can one evaluate targeted therapies in patients expected to have an excellent outcome? Should the goal be to improve response by adding a GSI to a multiagent chemotherapy backbone in NOTCH1-mutated T-ALL patients? To detect a change in EFS from 90% to 94%, one needs a clinical trial of approximately 1200 patients. It would take about 10 years for the Children's Oncology Group to accrue 1200 NOTCH1 mutant T-ALL patients. It seems more attractive to endeavor to replace components of therapy that have significant potential side effects with a novel agent such as a GSI and maintain equivalent outcome. How might a clinical trial be designed to answer this question? It has great relevance to other subtypes of childhood ALL. Not all molecularly targeted agents will be tested in patients with bad outcomesref
    Symptoms & signs : CNS involvement (10.5%, expecially intermediate forms)
    Laboratory examinations : Therapy : Prognosis : better than B-ALL (CR = 80%).
  • childhood T-ALL :
  • negative prognostic factors
  • positive prognostic factors :
  • adult T-ALL : with a median follow-up for surviving patients of 7.5 years, the probability of overall survival was 35.0% at 5 years. Not only the high-count group (> 50 x 109/l), but also the low-count group (< 3 x 109/l) showed a significantly lower survival rates than the intermediate-count group (p=0.0055 and 0.0037, respectively)ref. 56% of patients with pro-T + pre-T-ALL achieved CR compared with 91% for cortical + mature cases (P = .002). CD34 expression was associated with a significantly lower CR rate: 54% versus 84% (P = .009)ref
  • Web resources :
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