BCR-ABL1-positive chronic myeloid leukemia (CML) is a very rare disease in children. Currently, the long-term side effects of tyrosine kinase inhibitors (TKIs) and the duration of treatment in molecular responder (MR) patients are the major challenges in childhood CML. In our previous experience, the intermittent schedule of imatinib (3 weeks ON and one week OFF) was effective in reducing the long-term side effects and in improving MR. In addition, imatinib has been successfully discontinued in patients in persistent MR4.5-MR5. To confirm these results, we propose this international study that provides intermittent regimen of TKIs (any type) administered at the same dosage for 3 weeks ON and one week OFF in BCR-ABL1-positive CML patients with age at diagnosis
The primary aim is to reduce long-term side effects of TKIs. Bone metabolism, growth, endocrine and neurocognitive functions are evaluated at the beginning of the intermittent TKIs and, thereafter, at planned intervals.
The secondary aims are: 1) to maintain a stable MR4.5, and 2) to achieve MR4.5, despite the dose reduction with intermittent schedule; 3) to discontinue TKIs in patients in durable MR4.5-MR5; 4) to reduce the likelihood of early relapse in patients who discontinued TKIs; 5) to test pharmacokinetics of the TKIs; 6) to evaluate the Health-Related Quality of Life (HRQOL). Molecular monitoring for BCR-ABL1 transcript levelsi in peripheral blood is performed using qPCR at the standardised EUTOS laboratories, according to the EURO-SKI recommendations. The pharmacokinetics of TKIs are measured using validated high performance liquid chromatography methods at the beginning of the intermittent TKIs (baseline) and at the end of week OFF for 3 times. The HRQOL is assessed at planned intervals using the Pediatric Quality of Life Inventory Generic Core Scales.
Currently, the number of children successfully treated with TKIs is constantly increasing. The major challenge in childhood CML is to reduce treatment-related side effects and TKI discontinuation could represent a possibility to overcome this relevant clinical issue. However, reported outcomes from small cohorts of children after TKI discontinuation were suboptimal. Our experience with IM given 3 weeks a month suggests that this intermittent schedule is effective in reducing long-term side effects and in safety discontinuing treatment, representing a bridge before stopping treatment in CML children with durable deep molecular response.
This project has a potentially significant scientific and clinical impact to answer some outstanding issues regarding optimal management of children and adolescents with CML.
This international prospective study could permit the recruitment of a large number of patients in order to potentially confirm the safe and efficacy of the intermittent regimen of TKI, 3 weeks ON and one week OFF, in long-term treated children and adolescents with CML in durable molecular response.
In addition, this research provides the indications for molecular monitoring, according to established recommendations used in adults with CML.
The investigation of pharmacokinetics of TKI, imatinib and dasatinib, and the evaluation of the Health-Related Quality of Life (HRQOL) represent innovative research fields.
Since therapeutic drug monitoring has become an essential tool for the management of CML patients, pharmacokinetics of TKIs, imatinib and dasatinib, can be really useful for maximizing efficacy avoiding drug toxicity in long-term treated children and adolescents.
Since there is sparse data of HRQOL outcomes in children and young adults with CML, we have decided to explore the HRQOL using a well validated questionnaire for the age population of this study and available in all languages of participating countries.
Results of this research will be useful to better manage CML children and adolescents in durable deep molecular response and improve their clinical outcome.