Pediatr Blood Cancer. 2014 May 9. doi: 10.1002/pbc.25090. [Epub ahead of print]

Moser O, Krumbholz M, Thiede C, Tauer JT, Janz I, Lauten M, Dilloo D, Metzler M, Suttorp M.

How I treat: childhood CML. Jeffrey R. Andolina, Steven M. Neudorf and Seth J. Corey.
Blood, doi:10.1182/blood-2011-10-380774, Prepublished online December 30, 2011;

Chronic myeloid leukemia (CML) comprises 3% of pediatric leukemias, making evidence-based recommendations difficult. Imatinib has revolutionized the treatment for adult CML by eliminating allogeneic stem cell transplantation for almost all patients in chronic phase. Shown effective in pediatric CML, imatinib and successive tyrosine kinase inhibitors (TKI) have provided more therapeutic options. Because stem cell transplantation has been better tolerated in children and adolescents, the decision to treat by either TKI or transplantation is controversial. We present a recent case of a 12 month-old boy diagnosed with Bcr-Abl+ CML to highlight the controversies in treatment recommendations. We review the pediatric stem cell transplant outcomes as well as the pediatric experience with imatinib and other TKIs. Finally, we compare the side effects as well as costs associated with allogeneic stem cell transplant versus TKI therapy. We recommend that frontline therapy for pediatric CML in chronic phase is TKI therapy without transplantation. Patients in accelerated or blast crisis or who fail to reach landmarks on TKIs either because of intolerance or resistance should pursue stem cell transplantation. While we recommend adopting adult clinical experience to guide therapeutic decision making, the issues of infant CML, drug formulation, pharmacokinetics, and adolescent compliance merit clinical investigation.

Bone metabolism, growth rate and pubertal development in children with chronic myeloid leukemia treated with imatinib during puberty

Fiorina Giona, Stefania Mariani, Lucio Gnessi, Maria Luisa Moleti, Massimiliano Rea, Annalisa De Vellis, Deborah Marzella, Anna Maria Testi, and Robin Foa'

Haematologica 2012, DOI: 10.3324/haematol.2012.067447 4

...An altered bone and mineral metabolism, a reduction of testosterone and gynecomastia referred to PDGF-R and c-KIT inhibition in normal cells have been reported in adults treated with IM.2-4 So far, most of the data on the long-term side-effects of IM in children who have received IM concerns its impact on growth.5-7. We hereby report 4 CML pre-pubertal patients (3 males and 1 female; median age at the beginning of the IM, 10.6 years) in complete cytogenetic response (CCyR) with IM who were regularly monitored, between May 2004 and June 2011, to evaluate the bone and mineral metabolism, as well as growth and pubertal development. [...] In conclusion, the side effects observed in our patients (deceleration of longitudinal growth, reduction of BMD and fertility) raise some concerns that children long-exposed to IM prior to puberty may behave differently from adults. Since the number of children on treatment with TKIs is constantly increasing, DEXA, CTX, growth velocity in all patients, and FSH and inhibin-B in all males should be regularly monitored to plan the optimal treatment strategy in this category of patients.

Imatinib Has Adverse Effect on Growth in Children With Chronic Myeloid Leukemia; Deepak Bansal, Upender Shava, Neelam Varma, Amita Trehan, Marwaha; Pediatr Blood Cancer 2011, DOI 10.1002/pbc

Background. Long-term adverse effects of Imatinib in children with chronic myeloid leukemia (CML) are uncertain. The aim was to study the effect of imatinib on growth in children with CML.

Procedure. Children <= 13 years of age at diagnosis were enrolled retrospectively, from 2004 to 2011, from a single center in India. Patients who received imatinib for >1 year were included for growth assessment. Height standard deviation scores (SDS) were derived from WHO-AnthroPlus, a global growth monitoring tool.

Results. Thirty-four children received imatinib. Twenty children fulfilled the criteria for assessment of growth. Median age was 10 years (range: 2–13). Of 20 children, 13 were prepubertal at commencement of imatinib. The mean duration of imatinib in 20 children was 61.3 +- 16.2 months (range: 31–83). No patient was treated with a second-generation tyrosine kinase inhibitor or a stem cell transplant. Highly significant reduction in height SDS’s was observed (P = 0.002 at 5th year). Children who started imatinib therapy after the onset of puberty were immune to this adverse effect (P = 0.448 and 0.003 at 5th year of treatment for pubertal and prepubertal children, respectively). The 5-year survival probability of 33 children who received imatinib in chronic phase was 80% with a median survival time of 60 months (mean: 70.2; 95% CI: 60–80.5).

Conclusions. Growth retardation is a significant adverse effect of imatinib in children with CML. The failure to gain appropriate height was most discernible when imatinib was initiated in the prepubertal period. Etiology and remedial measures need to be investigated.