Prognostic Relevance of Genomic Aberrations and VH Mutation Status

To examine the individual prognostic value of genomic aberrations, the VH mutation status, and other clinical and laboratory features, a multivariate analysis was made of the survival time by means of a Cox regression (10). The VH mutation status, 17p deletion, 11q deletion, age, leukocyte count and lactate dehydrogenase levels were identified as independent prognostic factors in this analysis. When the VH mutation status, and 11q and 17p aberrations were included, the clinical stage of disease according to the systems of Rai or Binet was not identified as an independent prognostic factor. Similar results, demonstrating a very strong prognostic impact of the VH mutation status and genomic aberrations, were independently found in two other B-CLL series (140,141). Based on this model, four subgroups with widely differing survival probabilities can be defined by the VH mutation status, 11q deletion and 17p deletion (Fig. 7).

Table 2

Relation of Vh Mutation Status and Genomic Aberrations in 300 B-CLL Cases

Table 2

Relation of Vh Mutation Status and Genomic Aberrations in 300 B-CLL Cases

Mutated

Unmutated

(homology < 98%)

(homology > 98%)

Aberration

[n = 132 (44%)]

[n = 168 (56%)]

7 a p-value

Clonal aberrations

80

84

0.37

13q deletion

65

48

0.004

13q deletion single

50

26

< 0.001

Trisomy 12

15

19

0.44

11q deletion

4

27

< 0.001

17p deletion

3

10

0.03

17p or 11q deletion

7

35

< 0.001

aFisher's exact test.

From ref. 10, with permission.

aFisher's exact test.

From ref. 10, with permission.

Fig. 7. Probability of survival among patients in the following genetic categories: 17p- (17p deletion irrespective of VH mutation status), 11q- (11q deletion irrespective of VH mutation status), unmutated VH (VH homology >98% and no 17p or 11q deletion), and mutated VH (VH homology <98% and no 17p or 11q deletion). (A) Among all stages (n = 300) the estimated median survival times for the respective genetic subgroups were as follows: 17p deletion, 30 mo; 11q deletion, 70 mo; VH unmutated, 89 mo; and VH mutated, not reached (54% survival at 152 mo). (B) Among Binet stage A patients (n = 189) the estimated median survival times for the respective genetic subgroups were as follows: 17p deletion, 36 mo; 11q deletion, 68 mo; VH unmutated, 86 mo; and VH mutated, not reached (52% survival at 152 mo). (From ref. 10, with permission.)

Fig. 7. Probability of survival among patients in the following genetic categories: 17p- (17p deletion irrespective of VH mutation status), 11q- (11q deletion irrespective of VH mutation status), unmutated VH (VH homology >98% and no 17p or 11q deletion), and mutated VH (VH homology <98% and no 17p or 11q deletion). (A) Among all stages (n = 300) the estimated median survival times for the respective genetic subgroups were as follows: 17p deletion, 30 mo; 11q deletion, 70 mo; VH unmutated, 89 mo; and VH mutated, not reached (54% survival at 152 mo). (B) Among Binet stage A patients (n = 189) the estimated median survival times for the respective genetic subgroups were as follows: 17p deletion, 36 mo; 11q deletion, 68 mo; VH unmutated, 86 mo; and VH mutated, not reached (52% survival at 152 mo). (From ref. 10, with permission.)

These studies show that genomic aberrations and VH mutation status appear to have complementary relevance in estimating the prognosis in B-CLL. Unmutated VH and genomic aberrations were among the strongest prognostic factors and gives us insight into the biological bases of the clinical heterogeneity of B-CLL. For this reason, genomic aberrations and VH mutation status are currently being tested in relation to other clinical and laboratory factors in prospective multicenter studies of the German CLL Study Group (GCLLSG). If these factors allow us to predict the course of disease in individual patients at the time of diagnosis, independent of the stage, they could serve as the basis for future risk-adapted treatment strategies.

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