Polymorphisms in the Promoter Region of the Mcl-1 Gene Are Associated with Ex Vivo Cytotoxicity but Not with Response to Treatment in Advanced Chronic Lymphocytic Leukemia (CLL).

High levels of Mcl-1 have been related to a poor response to therapy in patients with CLL. Genetic polymorphisms in the promoter region of the Mcl-1 gene consisting in insertions of 6 (+6) or 18 (+18) bp have been described in 30% to 60% of patients with CLL. The biological and clinical translation of such polymorphisms is controversial. We have analysed this issue in a cohort of newly diagnosed patients with CLL (14 F/ 46 M; 80% in B or C Binet’s stage), treated with a combination of fludarabine (F), cyclophospamide (C) and mitoxantrone (M). Polymorphisms were correlated with: Mcl-1 RNA expression as assessed by quantitative PCR, ex vivo cytotoxicity against F, C, and M, alone or in combination, using the MTT assay, and clinical response to treatment. The frequency of the wild type (wt), +6, and +18 allel was 56%, 12%, and 32 %, respectively (table). Twenty-one of 60 (35%) patients were homozygous for wt allel. Quantification of Mcl-1 RNA expression was performed in 18 patients. Wt/wt patients (n=6) tended to have lower Mcl-1 gene expression than the remaining patients (1.0 AU ±0.4 vs 2.2 AU ±2.8). Ex vivo cytotoxicity was different according to the Mcl-1 genotypes for F, M, F+M, and C+F, but not for FCM. The highest cytotoxicity was observed in patients with +18/+18 genotype (n=7) while those with wt/wt (n=11) presented intermediate cytotoxicity and those with other genotypes (n=17) had the lowest cytotoxicity. Twenty-eight patients achieved CR, 22 PR, and 5 failed to respond. No relationship was found between Mcl-1 polymorphisms and response to therapy (table). Interestingly, however, the ex vivo response to F (58.2% ±16 vs 45.7% ±16, p=0.05) and F+M (87% ±9 vs 76% ±15.5, p=0.04) was greater in the 13 patients who achieved MRD-negative CR. After a median follow up of 28 months (range: 6–53), 16 of 38 patients have progressed. No relationship was found between Mcl-1 polymorphism and progression after treatment. In summary, in this series of patients with advanced CLL homogeneously treated the frequency of insertions in the promoter region of Mcl-1 gene was high. Although Mcl-1 polymorphisms were associated with the ex vivo response to antileukemic drugs, they did not correlate with response to treatment and disease progression.