aFor patients with del 13q as the sole genetic abnormality From Dohner et al8a aFor patients with del 13q as the sole genetic abnormality From Dohner et al8a compared with 7.7 years for patients with a clonal abnormality. Patients with complex karyotypic abnormalities had a poorer survival time than patients with either a normal karyotype or a single abnormality. When patients with single abnormalities only were studied, those with trisomy 12 had a poorer prognosis than patients with abnormalities of chromosome 13 or those with a normal karyotype.69'70 Subsequent cytogenetic and interphase FISH studies have confirmed the association between abnormalities of chromosome 13q14 and prolonged survival.71 However, the influence of trisomy 12 on survival remains controversial. Criel et al.72 found trisomy 12 to be an adverse prognostic factor only in patients with typical lymphocyte morphology. In a multivariate analysis that included both trisomy 12 and lymphocyte morphology, only lymphocyte morphology retained prognostic significance.73

In 1997 two studies29,74 reported that deletion of 11q22-23 was associated with rapid disease progression and poor survival. In addition, patients with 11q deletions presented at a younger age and with more advanced disease, particularly with bulky lymphadenopathy. Of particular interest was the finding that the poor survival of patients with 11q deletion was confined to patients less than 55 years of age. The explanation for the impact of age on survival is unclear because in general younger patients with CLL do not have a more aggressive disease than elderly patients.

In the CLL3 trial of the German CLL Study Group, which is investigating the role of autologous stem cell transplantation, del (11q23) was associated with molecular evidence of persistent disease in 38 percent of patients postautograft compared with only 6 percent of patients without an abnormality of chromosome 11q (p <.014).75

El Roubey et al.76 first demonstrated that p53 mutations in CLL were associated with poor clinical outcome. Many subsequent studies have confirmed the association between p53 loss and/or mutation with advanced clinical stage, an increase in circulating prolymphocytes, rapid disease progression, a poor response to therapy with alkylating agents and purine analogues, and short survival.77-79 A German multicenter randomized trial of fludarabine versus fludarabine plus epirubicin treatment demonstrated an overall response rate of 81 percent. In patients with del (17)(p13) detected by interphase FISH, the response rate was 25 percent compared with 87 percent without this abnormality (p <.001)80 Pettitt et al.38 showed in vitro that CLL cells with a p53 mutation and spleen cells from p53 knockout mice were only partially resistant to purine analogue-induced killing. They postulated that in vivo drug resistance to purine analogues was more likely to be due to development of additional genetic abnormalities as a consequence of the genomic instability associated with p53 mutation than to a direct consequence of p53 dysfunction.

Patients with chromosome 6q deletions have a higher white cell count and more extensive lymphadenopathy than patients without 6q deletions, but there is no impact on either treatment-free or overall survival.46

The results of the most comprehensive study of genetic abnormalities in 325 cases of CLL analyzed by interphase FISH for deletions of 6q, 11q, 13q, and 17p, trisomies of 3q, 8q, and

12q, and translocations involving 14q32 are shown in Table 6-6. In a multivariate study both 11q and 17p deletions were independent prognostic factors.81

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