Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the only proven cure for chronic myeloid leukemia (CML), a rare malignancy in childhood. With the excellent results induced by ...the tyrosine kinase inhibitor (TKI) imatinib in adults in the last decade, the appropriate management of children with CML has also changed radically, and only a minority are now transplanted as a front-line treatment. Data on pediatric experiences with imatinib in CML from controlled trials remain very limited, but this review of available data describes the role of imatinib in children with CML, addressing: 1) the starting dose; 2) pharmacokinetics in childhood; 3) possible adverse effects, with a focus on the still-growing skeleton; 4) early monitoring of treatment efficacy in an attempt to avoid failure; 5) the timing of allo-SCT in children; and 6) treatment of CML relapse after allo-SCT. Because the characteristics of CML in children seem to overlap extensively with what is described in adult internal medicine, most answers and pediatric algorithms are adapted from the treatment of CML in adults. Today in 2010, allo-SCT in children should be postponed until CML becomes refractory to imatinib. The approach for young patients with suboptimal responses is unclear because data on the efficacy and safety of second-generation TKIs in childhood are almost entirely missing. Other than being included in a formal trial on second-generation TKIs, allo-SCT for patients failing imatinib remains the first choice.
Depending on the analytical tool applied, the hallmarks of chronic myeloid leukemia (CML) are the Philadelphia Chromosome and the resulting mRNA fusion transcript BCR-ABL1. With an incidence of 1 per ...1 million of children this malignancy is very rare in the first 20 years of life. This article aims to; (i) define the disease based on the WHO nomenclature, the appropriate ICD 11 code and to unify the terminology, (ii) delineate features of epidemiology, etiology, and pathophysiology that are shared, but also differing between adult and pediatric patients with CML, (iii) give a short summary on the diseases to be considered as a differential diagnosis of pediatric CML, (iv) to describe the morphological, histopathological and immunophenotypical findings of CML in pediatric patients, (v) illustrate rare but classical complications resulting from rheological problems observed at diagnosis, (vi) list essential and desirable diagnostic criteria, which hopefully in the future will help to unify the attempts when approaching this rare pediatric malignancy.
Chronic myeloid leukaemia (CML) is very rare in children. The aim of the study is to report the experience within the I-CML-Ped study in children and adolescents presenting at diagnosis with advanced ...phase disease and to describe their characteristics and outcomes.
Of 479 children and adolescents enrolled in the international registry for childhood chronic myeloid leukaemia (I-CML-Ped Study; www.clinicaltrials.govNCT01281735), 36 children (7.5%) presented at initial diagnosis with CML in advanced phase according to the European LeukemiaNet criteria.
Nineteen (4%) patients were diagnosed in accelerated phase (CML-AP), and among the 17 patients (3.5%) diagnosed in blastic phase (CML-BP), 70% presented with lymphoid immunophenotype. Initial treatment of CML-AP/CML-BP consisted of tyrosine kinase inhibitors (TKIs) with or without chemotherapy, leading to complete haematologic response in 33 of 36 (92%) patients. Seventeen patients proceeded to haematopoietic stem cell transplantation. At the last follow-up, 18 of 19 patients with de novo CML-AP are alive in at least major molecular response (MMR) (n = 16), in progression (n = 1) or in molecular relapse (n = 1) and 13 of 17 patients with de novo CML-BP are alive in at least MMR. Five-year overall survival rates are 94% (95% confidence interval CI: 66%–99%) and 74% (95% CI: 44%–89%) for patients diagnosed in CML-AP and CML-BP, respectively.
Children with advanced phase at diagnosis of CML seem to have a better survival rate than that reported for advanced phases evolving under TKI treatment.
•Children with de novo advanced phases of chronic myeloid leukaemia.•De novo advanced phases of chronic myeloid leukaemia seem to have a better outcome.•Early haematopoietic stem cell transplantation could be avoided in some children.•Lymphoid immunophenotype predominates in de novo blast phase chronic myeloid leukemia.
Ponatinib is effective in adults with Philadelphia chromosome–positive (Ph+) leukaemias, but scant data are available regarding the use of this tyrosine kinase inhibitor in children.
The aim of this ...study isto describe the tolerance and efficacy of compassionate use of ponatinib in a paediatric cohort of patients with Ph+ leukaemias.
Data from 11 children with chronic myeloid leukaemia (CML) registered to the international registry of childhood chronic myeloid leukaemia and from 3 children with Ph+ acute lymphoblastic leukaemia (Ph+ ALL) treated with ponatinib were collected retrospectively.
In 11 girls and 3 boys (median age 14 years), ponatinib was used as a second- to eighth-line treatment. Ponatinib was administered as single therapy (9 patients) or in combination with chemotherapy (8 patients). The status of the disease when ponatinib was started was as follows: CML in advanced phases (n = 8), CML in chronic phase without achievement of molecular response (n = 2) or presence of T315I mutation (n = 1) and Ph + ALL in molecular (n = 1) or marrow (n = 2) relapses. The median dose administered was 21.4 mg/m2 and median duration of ponatinib was 2.5 months. Ponatinib alone or in combination with chemotherapy administered on 16 occasions led to achievement of major molecular response in 50% of cases. Ponatinib was used as a bridge to transplant in 4 cases. Among the 9 patients treated with ponatinib alone, toxicity grade III–IV (2 patients) was exclusively haematologic. No vascular events related to ponatinib were observed.
Ponatinib may be a reasonable additional treatment option for children with Ph+ leukaemias who have failed several lines of therapy.
•Ponatinib induces responses in children with heavily pretreated children Philadelphia chromosome–positive (Ph+) leukaemias.•Ponatinib could be used as a bridge to transplant in childhood Ph+ leukaemias.•Toxicity of ponatinib is mainly haematologic in children with Ph+ leukaemias.
Chronic myeloid leukaemia in children and young people is a relatively rare form of leukaemia that shows increased incidence with age and some evidence suggests that the molecular basis differs from ...that in adults. Significant advances in targeted therapy with the development and use in children of tyrosine kinase inhibitors and the ability to monitor and understand the prognostic significance of minimal residual disease by standardized molecular techniques has shifted the management of this condition from bone marrow transplantation as the main therapeutic modality to individualized treatment for each patient based on achieving specific milestones. The physiological changes occurring during childhood, particularly those affecting growth and development and the long-term use of treatment, pose specific challenges in this age group, which we are only beginning to understand.
Chronic myeloid leukemia (CML) in minors is a rare disease which can be effectively treated by tyrosine kinase inhibitors (TKIs) since the year 2000. A majority of pediatricians will encounter one or ...two CML patients in the course of their careers and will typically have to rely on written information along with their own intuition to provide care. Knowledge of response to TKIs and of age-specific side effects has an impact on the design of pediatric CML trials in many ways aiming to contribute toward greater predictability of clinical improvements. Information from a registry on a rare disease like CML offers the enormous benefit of enabling treating physicians to interact and share their collective experience. The International Registry on Pediatric CML (IR-PCML) was founded at Poitiers/France almost 10 years ago. Since then, the number of collaboration centers and in parallel of registered patients continuously increased (> 550 patients as of December 2019). Ideally, from a given treatment center in a country data are transferred to a national coordinator who interacts with the IR-PCML. In the sense of quality assurance, the registry can offer dissemination of knowledge on state-of-the-art diagnostics (including reference appraisal), optimal treatment approaches, and follow-up procedures within a network that is exerting its strength via participation. With continuous growth during the recent years, very rare subgroups of patients could be identified (e.g., CML diagnosed at age < 3 years, children presenting with specific problems at diagnosis or during course of treatment) which had not been described before. Publications coming from the IR-PCML disseminated this useful information derived from patients who robustly participate and share information about their disease, among themselves and with their caregivers and clinicians. Patient input driving the collection of data on this rare leukemia is the basis for the considerable success of bringing new therapeutics into clinical use.
The tyrosine kinase inhibitor (TKI) imatinib was rationally designed to target BCR-ABL1 which is constitutively activated in chronic myeloid leukemia (CML). Following the tremendous success in ...adults, imatinib also became licensed for treatment of CML in minors. The rarity of pediatric CML hampers the conduction of formal trials. Thus, imatinib is still the single TKI approved for CML treatment in childhood. Areas covered: This review attempts to provide an overview of the literature on pharmacology, pharmacokinetic, and pharmacogenetic of imatinib concerning pediatric CML treatment. Articles were identified through a PubMed search and by reviewing abstracts from relevant hematology congresses. Additional information was provided from the authors' libraries and expertise and from our own measurements of imatinib trough plasma levels in children. Pharmacokinetic variables (e.g. alpha 1-acid glycoprotein binding, drug-drug/food-drug interactions via cytochrome P450 3A4/5, cellular uptake mediated via OCT-1-influx variations and P-glycoprotein-mediated drug efflux) still await to be addressed in pediatric patients systematically. Expert commentary: TKI response rates vary among different individuals and pharmacokinetic variables all can influence CML treatment success. Adherence to imatinib intake may be the most prominent factor influencing treatment outcome in teenagers thus pointing towards the potential benefits of regular drug monitoring.
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