Response to Therapy and Survival in CLL Is Influenced by Genetic Markers. Preliminary Analysis from the LRF CLL4 Trial.
Authors: Catovsky Daniel , Richards Sue , Matutes Estella , Burford Anna , Brito-Babapulle Vasantha , Dearden Claire , Morris Philip , Pettitt Andrew 
Published: October 2019

Abstract
The randomised CLL4 trial was launched in 1999 to answer scientific and management issues. Since then, 730 patients with Binet stages A progressive, B and C have been randomised between 1) chlorambucil (10mg/m2 x 7 days), or 2) fludarabine (FDR) alone (40mg/m2 x 5 d oral or 25mg/m2 x 5 days IV), or FDR plus cyclophosphamide (FDR 24mg/m2 x 5 d oral or 25mg/m2 x 3 d IV plus cyclo 150mg/m2 x 5 d oral or 250mg/m2 x 3 d IV). Information on FISH analysis with 5 probes is available on 440 patients. The incidence of the genetic abnormalities is: 13q del (60%), trisomy 12 (15%), 6q del (8%), 11q del (19%), 17p del (11%); some markers are positive in more than one patient. Analysis by stage showed no differences in the distribution of these markers and analysis by age showed that patients with 13q del were younger (p=0.006) and those with 11q del were older (p=0.01). Analysis by response to all therapies (as the code of individual therapies has not been broken) in 343 patients is shown in Table 1.
The results show clearly that almost half the patients with 17p del (p53 locus) are primary non-responders (NR) or show progressive disease (PD) following first line therapy, and have poor survival. 2yr survival of patients with none of these abnormalities was 87% (79%–95%), and using a hierarchical model with normals as the fifth group there was a clear trend in survival between groups (2p<0.00005).
When the % of 17p del lymphocytes was correlated with response, it was apparent that the higher the % of 17p del cells the greater the proportion of non-responders (Table 2), with 20% 17p del being the critical threshold.
When we grouped together cases with 6q, 11q and 17p deletion plus trisomy 12 (representing 42% of cases) there was a significantly lower response rate compared with the cases without those four abnormalities: CR/Nod PR 35% vs 47%, PR 33% vs 39%, and 32% vs 13%, (Chi-square 13.3; p=0.0003). This study demonstrates that the genetic abnormalities which can be shown in c.80% of patients with active CLL have a significant bearing on the response to treatment and early survival, confirming the survival differences reported by Dohner at al (N Engl J Med 343: 1910–16; 2000). It remains to be determined whether better therapies could overcome the low response rates of patients with poor prognostic genetic abnormalities.
Table 1: FISH analysis by response (non-hierarchical) and survival
Abnormality CR/Nod PR PR NR/PD p value* 2 yr survival (95% CI) * Analysis of individual abnormalities versus the rest; Chi-square test; **326 patients 17p del 33% 18% 48% 0.004 67% (50%–85%) 11q del 29% 44% 27% NS 73% (59%–86%) Trisomy 12 41% 31% 29% NS 72% (57%–87%) 6q del** 39% 29% 32% NS 75% (56%–95%) 13q del 42% 37% 21% NS 91% (86%–95%)
Table 2: Correlation of response with proportion of 17p del lymphocytes
% deletion No. cases CR/Nod PR PR NR/PD Chi-square 318.8; p<0.0001 <5 (negative) 310 43% 39% 18% 5–20 18 61% 22% 17% >20–100 15 0% 13% 87%