Del 11Q anomalie génétique

L'anomale génétique DEl 11q (20% des cas)
   Cette anomalie des cellules leucémiques est de mauvais pronostique
         Parce que un des deux chromosome 11 perd le gène qui code la protéine ATM: et cette protéine est le vecteur d'action de la plus part des médicaments (fludarabine, chlorambucil and rituximab).

         Donc dans un premier temps les médicaments peuvent être efficaces parce qu'un seul des deux chromosomes est altéré.
         Dans les mauvais cas les deux chromosomes ont la même délétion, les traitements "standards" sont inefficaces, ce qui peut arriver après un premier traitement.

         Mais les patients on une tendance a avoir un temps de rémission raccourci. La solution sera une seconde série du même traitement qui peut être efficace mais le risque d'immunodéficience augmente.  Alors peut être les nouveaux traitements devront être essayés. Ou une allogreffe de moelle



On the other hand patients with del 11q tend to respond well, but they also tend to relapse earlier than other patients. This may be because there is an increased tendency for these patients to acquire an ATM defect on the other chromosome 11. The problem then becomes how should such patients be retreated. Another round of FCR or perhaps PCR will put most patients back in remission, but being exposed to these drugs a second time raises risk of immunodeficiency and marrow failure. Perhaps these patients should be the ones in whom clinical trials of newer agents should take place. Drugs like HuMax, Revlimid and flavopiridol might be tried. Newer drugs that inhibit the enzyme PARP1 look promising in the laboratory, and I hope they will shortly make an appearance in the clinic. T Hambling
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11q23 Deletion. Deletion of the long arm of chromosome 11 is detected in 5–20% of CLL patients [2, 15, 45]. These deletions are highly variable in size, being larger than 20 megabases in most cases [46, 47]. The MDR includes 11q22.3- q23.1 chromosome bands, thus harboring the ATM gene in almost all cases, as well as other genes including RDX, FRDX1, RAB39, CUL5, ACAT, NPAT, KDELC2, EXPH2, MRE11, H2AX, and BIRC3 (Figure 1). Indeed, cases can be classified in “classical or large deletion” (more common) and “atypical or small deletion” (uncommon and more frequently associated with ATM mutations). It is remarkable that no homozygous 11q deletions have been described. Regarding the association between del(11q) and other chromosomal abnormalities, such cases show an increased copy number alterations, thus indicating genomic instability [15, 48].ATM gene mutations have been largely studied in CLL patients with del(11q); however, they have been found in only 8–30%
of 11q- patients [49], indicating that other genes could play a role in the pathobiology of 11q deletions in CLL. One of these genes is BIRC3, which is located near toATM gene, at 11q22. BIRC3 disrupting mutations and deletions have been rarely detected in CLL at diagnosis (4%) but detected in 24% of fludarabine-refractory CLL patients (Figure 1). Interestingly, progressive but fludarabine-sensitive patients did not show BIRC3 aberrations, suggesting that BIRC3 genetic lesions are specifically associated with a chemorefractory CLL phenotype [50]. In addition, it is remarkable that patients with BIRC3 lesions are mutually exclusive with CLL patients harboring TP53 abnormalities. However, a recent study by
Rose-Zerilli et al. has shown thatATM mutations rather than BIRC3 deletion and/or mutation had impact on overall and progression-free survival in 11q-deleted CLL patients treated with first-line therapy [51].

From a clinical point of view, CLL patients with del(11q) are characterized by large and multiple lymphadenopathies and have been associated with poor prognostic factors, such as unmutated IGHV genes  Regarding the prognostic significance, the presence of del(11q) implies clinically
progressive disease in almost all cases. In addition, those 11q- cases have been associated with shorter TTFT, shorter remission durations, and shorter OS following standard chemotherapy compared to nondeleted 11q (and nondeleted 17p) cases [52]. However, more recent treatments based on chemoimmunotherapy may overcome the adverse prognostic significance of 11q deletion in previously untreated patients. It has been reported that del(11q) does not have impact on progression-free survival (PFS); however, there is still a lack of information regarding long-term OS studies. Moreover, genetic heterogeneity displayed in patients with del(11q) may impact on long-term clinical outcome (Table 1) [53]