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.

Summary: Additional data on blast phase (BP) chronic myeloid leukaemia (CML) in children and adolescents is essential for improving diagnostic and therapeutic approaches of this rare but serious condition. Here, we describe distinct clinical and genetic characteristics of 18 paediatric patients with de novo (n = 10) and secondary (n = 8) BP CML enrolled in the CML‐PAED‐II trial and registry. Our findings suggest that paediatric patients exhibit a diverse cytogenetic profile compared to adults with BP CML. In addition, patients with de novo BP CML in this cohort presented at a younger age, whereas patients with secondary BP CML more often harboured complex karyotypes.

Philadelphia chromosome-positive chronic myeloid leukemia (CML) is cytogenetically characterized by the classic translocation t(9;22)(q34;q11), whereas additional non-Philadelphia aberrations (nPhAs) have been studied extensively in adult patients with CML, knowledge on nPhAs in pediatric patients with CML is still sparse. Here, we have determined nPhAs in a cohort of 161 patients younger than 18 years diagnosed with chronic phase CML and consecutively enrolled in the German national CML-PAED-II registry. In 150 cases (93%), an informative cytogenetic analysis had been performed at diagnosis. In total, 21 individuals (13%) showed nPhAs. Of these, 12 (8%) had a variant translocation, 4 (3%) additional chromosomal aberrations (ACAs) and 5 (3%) harbored a complex karyotype. Chromosome 15 was recurrently involved in variant translocations. No significant impact of the cytogenetic subgroup on the time point of cytogenetic response was observed. Patients with a complex karyotype showed an inferior molecular response compared to patients carrying the classic translocation t(9;22)(q34;q11), variant translocations or ACAs. No significant differences in the probability of progression-free survival and overall survival was found between patients with nPhAs and patients with the classic Philadelphia translocation only. Our results highlight the distinct biology of pediatric CML and underline the need for joint international efforts to acquire more data on the disease pathogenesis in this age group.

The cellular reconstitution after childhood cancer therapy is associated with the risk of infection and efficacy of revaccination. Many studies have described the reconstitution after stem cell transplantation (SCT). The recovery after cancer treatment in children who have not undergone SCT has mainly been investigated in acute lymphoblastic leukemia (ALL), less for solid tumors. Here, we have examined the temporal evolution of total leukocyte, neutrophil and lymphocyte counts as surrogate parameters for the post-therapeutic immune recovery in a cohort of n = 52 patients with ALL in comparison to n = 58 patients with Hodgkin’s disease (HD) and n = 22 patients with Ewing sarcoma (ES). Patients with ALL showed an efficient increase in blood counts reaching the age-adjusted lower limits of normal between 4 and 5 months after the end of maintenance therapy. The two groups of patients with HD and ES exhibited a comparably delayed recovery of total leukocytes due to a protracted post-therapeutic lymphopenia which was most pronounced in patients with HD after irradiation. Overall, we observed a clearly more efficient resurgence of total lymphocyte counts in patients aged below 12 years compared to patients aged 12 to 18 years. Our results underline that the kinetics of cellular reconstitution after therapy for HD and ES differ significantly from ALL and depend on treatment regimens and modalities as well as on patient age. This suggests a need for disease, treatment, and age specific recommendations concerning the duration of infection prophylaxis and the timing of revaccination.

Summary: Imatinib (IMA) therapy for paediatric chronic myeloid leukemia (pCML) requires age‐dependent dose adjustments. Assessment of therapeutic drug monitoring (TDM) under ‘real‐world’ conditions was performed. Collection of blood and TDM‐relevant data, calculation of individual dosage exposure, measurement of plasma C _min (IMA, Nor‐IMA) by HPLC/MS‐MS and recording of adverse event (AE). Two hundred and forty‐six specimens from 66 patients were analysed. Individual median IMA dosage exposure was 253 mg/m ² (range: 128–504). Children <13 years received a median of 43 mg/m ² more than older patients ( p < 0.0001). Median C _min of IMA and Nor‐IMA was 1017 ng/mL (range: 51–3976) and 269 ng/mL (range: 21–981), respectively, correlating significantly with the prescribed dose. At 5/246 visits, non‐adherence was confirmed by very low IMA C _min in 3/66 patients, all ≥13 years old. Correlation of IMA C _min >1000 ng/mL with achieving OMR demonstrated in each 63% ( N = 24/37, N = 27/43, respectively) patients at months 3 and 6. In the cohort with lower levels, only 23% and 50%, respectively, achieved these milestones. This difference was significant only at month 3. Of 66 patients, 30 reported 125 AEs with gastrointestinal and musculoskeletal as leading complaints. In 9.3% of AEs, the correlated IMA C _min was ≥3000 ng/mL. TDM is a simple and rapid additional tool for managing pCML under ‘real‐world conditions’.