Optimal management for pediatric chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) is rare among childhood leukemias. Its incidence increases with age, from 0.09/100 000 at ≤15 years old to 7.88/100 000 at ≥75 years old. There are several biological and clinical differences between pediatric and adult CML. Markedly increased leukocyte count and a higher incidence of splenomegaly are characteristic features at diagnosis in pediatric patients. The therapeutic approach to CML has changed since the introduction of the tyrosine kinase inhibitor (TKI) imatinib, followed by dasatinib and nilotinib. Given the efficacy of TKI in adult CML, TKI are regarded as the established first-line treatment in adult patients. In 2011, a prospective phase IV study in pediatric patients showed the excellent efficacy and safety of imatinib. Imatinib is also accepted as a first-line option for childhood chronic phase CML. Although the efficacy of dasatinib and nilotinib reported in adult studies seems very attractive for pediatric patients, neither drug has been prospectively investigated in a large pediatric cohort. TKI are designed to inhibit BCR-ABL1 kinase, but they have unfavorable effects, so-called "off-target" complications, such as growth impairment. Long-term morbidity due to TKI is unknown. Furthermore, the adverse effects on growing children have not been clearly elucidated, even though the exposure period to imatinib is relatively short. To establish the standard therapeutic management for pediatric CML, it is important to prospectively confirm the attractive outcomes obtained in adult studies via pediatric clinical trials with a careful monitoring system for TKI-induced adverse effects, especially in growing children.

Sequential use of second‐generation tyrosine kinase inhibitors following imatinib therapy in pediatric chronic myeloid leukemia: A report from the Japanese Pediatric Leukemia/Lymphoma Study Group

“…Although there are limited data regarding the use of nilotinib and dasatinib in children, for CP‐CML patients with suboptimal response, failure, or intolerance to imatinib, the next choice is 2G‐TKIs rather than HSCT . The pediatric dose of dasatinib is 60–80 mg/m 2 per day in previous and ongoing clinical studies, while the ongoing global phase II trial with nilotinib in CML pediatric patients uses a starting dose of 230 mg/m 2 b.i.d . The proportion of our patients who were diagnosed after March 2009 and discontinued imatinib thereafter was 37%, slightly more than the 30% that has been reported for children in a French prospective trial .…”

“…There is no information for nilotinib with regard to the severity and frequency of these complications in the pediatric setting, because of the lack of retrospective analyses involving this agent . A prospective trial of nilotinib (NCT01844765) is ongoing.…”

Management of chronic myeloid leukemia in children and adolescents: Recommendations from the Children's Oncology Group CML Working Group

“…This was followed by a descriptive literature review of original studies and expert opinion manuscripts evaluating management and outcome of CML in children and adolescents. In addition, published guidelines, guidance documents, and standard of care documents for the management of adults with CML were reviewed . The data gathered were presented and reviewed within the COG CML Working Group.…”

“…For adult patients, imatinib, dasatinib, nilotinib, and bosutinib are all FDA approved as frontline therapy and are recommended for frontline treatment according to the NCCN guideline . Until recently, imatinib was the only FDA‐approved TKI for first‐line therapy in children with CML . Dasatinib was approved by the FDA as first‐ and second‐line therapy for pediatric patients with CP CML in 2017 .…”

The Case of Chronic Myeloid Leukemia in a Child of 2 Years

“…Проблема долгосрочных побочных эффектов тера-пии ИТК у детей связана с постоянной ингибицией различных физиологически активных тирозинкиназ в развивающемся и растущем организме, которая мо-жет реализовываться в пока неизвестные клиниче-ские эффекты [5]. Известно, что иматиниб имеет ряд побочных эффектов, один из которых влияние на ми-нерализацию костной ткани, формирование скелета и соответственно на рост и развитие детского организ-ма [6]. ИТК могут оказывать тератогенный эффект, и, хотя нет достоверных исследований в этой обла-сти, женщинам фертильного возраста рекомендует-ся избегать беременности во время приема ИТК [5].…”