Increased cell proliferation is a hallmark of acute lymphoblastic leukemia (ALL), and genetic alterations driving clonal proliferation have been identified as prognostic factors. To evaluate replicative history and its potential prognostic value, we determined telomere length (TL) in lymphoblasts, B-, and T-lymphocytes, and measured telomerase activity (TA) in leukocytes of patients with ALL. In addition, we evaluated the potential to suppress the in vitro growth of B-ALL cells by the telomerase inhibitor imetelstat. We found a significantly lower TL in lymphoblasts (4.3 kb in pediatric and 2.3 kb in adult patients with ALL) compared to B- and T-lymphocytes (8.0 kb and 8.2 kb in pediatric, and 6.4 kb and 5.5 kb in adult patients with ALL). TA in leukocytes was 3.2 TA/C for pediatric and 0.7 TA/C for adult patients. Notably, patients with high-risk pediatric ALL had a significantly higher TA of 6.6 TA/C compared to non-high-risk patients with 2.2 TA/C. The inhibition of telomerase with imetelstat ex vivo led to significant dose-dependent apoptosis of B-ALL cells. These results suggest that TL reflects clonal expansion and indicate that elevated TA correlates with high-risk pediatric ALL. In addition, telomerase inhibition induces apoptosis of B-ALL cells cultured in vitro. TL and TA might complement established markers for the identification of patients with high-risk ALL. Moreover, TA seems to be an effective therapeutic target; hence, telomerase inhibitors, such as imetelstat, may augment standard ALL treatment.

In a phase-2 study, the telomerase inhibitor imetelstat induced rapid hematologic responses in all patients with essential thrombocythemia who were refractory or intolerant to prior therapies. Significant molecular responses were achieved within 3-6 months in 81% of patients with phenotypic driver mutations in JAK2, CALR and MPL. Here, we investigated the dynamics of additional somatic mutations in response to imetelstat. At study entry, 50% of patients carried 1-5 additional mutations in the genes ASXL1, CBL, DNMT3A, EZH2, IDH1, SF3B1, TET2, TP53 and U2AF1. Three patients with baseline mutations also had late-emerging mutations in TP53, IDH1 and TET2. Most clones with additional mutations were responsive to imetelstat and decreased with the driver mutation, including the poor prognostic ASXL1, EZH2 and U2AF1 mutations while SF3B1 and TP53 mutations were associated with poorer molecular response. Overall, phenotypic driver mutation response was significantly deeper in patients without additional mutations (P = 0.04) and correlated with longer duration of response. In conclusion, this detailed molecular analysis of highly pretreated and partly resistant patients with essential thrombocythemia reveals a high individual patient complexity. Moreover, imetelstat demonstrates potential to inhibit efficiently co-incident mutations occurring in neoplastic clones in patients with essential thrombocythemia. (ClinicalTrials.gov number, NCT01243073. N Engl J Med 2015; 373:920-928, DOI: 10.1056/NEJMoa1503479.)