Favourable outcome of de novo advanced phases of childhood chronic myeloid leukaemia

Background: 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. Methods: Of 479 children and adolescents enrolled in the international registry for childhood chronic myeloid leukaemia (I-CML-Ped Study; www.clinicaltrials.gov NCT01281735), 36 children (7.5%) presented at initial diagnosis with CML in advanced phase according to the European Leukemia Net criteria. Results: 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. Conclusion: 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

Studying Side Effects of Tyrosine Kinase Inhibitors in a Juvenile Rat Model with Focus on Skeletal Remodeling

The tyrosine kinase (TK) inhibitor (TKI) imatinib provides a highly effective treatment for chronic myeloid leukemia (CML) targeting at the causative oncogenic TK BCR-ABL1. However, imatinib exerts off-target effects by inhibiting other TKs that are involved, e.g., in bone metabolism. Clinically, CML patients on imatinib exhibit altered bone metabolism as a side effect, which translates into linear growth failure in pediatric patients. As TKI treatment might be necessary for the whole life, long-term side effects exerted on bone and other developing organs in children are of major concern and not yet studied systematically. Here, we describe a new juvenile rat model to face this challenge. The established model mimics perfectly long-term side effects of TKI exposure on the growing bone in a developmental stage-dependent fashion. Thus, longitudinal growth impairment observed clinically in children could be unequivocally modeled and confirmed. In a “bench-to-bedside” manner, we also demonstrate that this juvenile animal model predicts side effects of newer treatment strategies by second generation TKIs or modified treatment schedules (continuous vs. intermittent treatment) to minimize side effects. We conclude that the results generated by this juvenile animal model can be directly used in the clinic to optimize treatment algorithms in pediatric patients

Lymphoblastic predominance of blastic phase in children with chronic myeloid leukaemia treated with imatinib:A report from the I-CML-Ped Study

Background: Chronic myeloid leukaemia (CML) is a rare disease in children. The frequency and outcome of children evolving to accelerated phase (AP) or blastic phase (BP) under treatment with imatinib is unknown. The aim of the current study is to assess the inci-dence of progression from CML in chronic phase with imatinib frontline in a paediatric setting and describe the management and outcome of these patients. Patients and methods: In the I-CML-Ped Study database (www.clinicaltrials.gov, #NCT01281735), 19 of 339 paediatric patients in chronic phase treated with imatinib in the frontline evolved to CML-AP or CML-BP. Results: With a median follow-up of 38 months (range: 2-190 months), the cumulative inci-dence of progression at 1 and 3 years was 3% (confidence interval [CI] 95%: 1-5%) and 7% (CI 95%: 4-11%), respectively. We observed a large predominance of lymphoid-BP (70%) over myeloid-BP (30%) with imatinib in frontline therapy. Sixteen patients underwent haemato-poietic stem cell transplantation, and eight were treated with a tyrosine kinase inhibitor after transplant. Only the transplanted patients are alive. The 5-year overall survival rate of children with CML-AP/BP is 44%, with no statistical difference between the lymphoid-BP and myeloid-BP outcome. Conclusion: Children evolving to AP or BP under treatment with imatinib have a very poor prognosis with an overall survival under 50%, much worse than children with advanced phase at diagnosis. (c) 2020 Elsevier Ltd. All rights reserved

Prognostic discrimination based on the EUTOS long-term survival score within the International Registry for Chronic Myeloid Leukemia in children and adolescents

The EUTOS Long-Term Survival score was tested in 350 children with chronic myeloid leukemia in first chronic phase treated with imatinib and registered in the International Registry for Childhood Chronic Myeloid Leukemia. With a median follow up of 3 years (range, 1 month to 6 years) progression and/or death (whichever came first) occurred in 23 patients. For the entire cohort of patients the 5-year progression-free survival rate was 92% (95% CI: 87%-94%) and the 5-year survival accounting for chronic myeloid leukemia deaths was 97% (95% CI: 94%-99%). Of the 309 patients allocated to low (n=199), intermediate (n=68) and high (n=42) risk groups by the EUTOS Long-Term Survival score, events (progression and/or death) occurred in 6.0%, 8.8% and 26.2%, respectively. Estimates of the 5-year progression-free survival rates according to these three risk groups were 96% (95% CI: 92%- 98%), 88% (95% CI: 76%-95%) and 67% (95% CI: 48%-81%), respectively. Differences in progression-free survival according to these risk groups were highly significant (P<0.0001, overall). The EUTOS LongTerm Survival score showed better differentiation of progression-free survival than the Sokal (<45 years), Euro and EUTOS scores in children and adolescents with chronic myeloid leukemia and should be considered in therapeutic algorithms

The Other Press, February 28, 1977

BACKGROUND: In the adult population with newly diagnosed chronic myeloid leukemia (CML), variant translocations are usually not considered to be impairing the prognosis, whereas some additional cytogenetic abnormalities (ACAs) are associated with a negative impact on survival. Because of the rarity of CML in the pediatric population, such abnormalities have not been investigated in a large group of children with CML. METHODS: The prognostic relevance of variant t(9;22) and ACAs at diagnosis was assessed in 301 children with CML in the chronic phase who were enrolled in the International Registry for Chronic Myeloid Leukemia in Children and Adolescents. RESULTS: Overall, 19 children (6.3%) presented with additional cytogenetic findings at diagnosis: 5 children (1.7%) had a variant t(9;22) translocation, 13 children (4.3%) had ACAs, and 1 had both. At 3 years, for children with a classic translocation, children with ACAs, and children with a variant t(9;22) translocation who were treated with imatinib as frontline therapy, the probability of progression-free survival (PFS) was 95% (95% confidence interval [CI], 91%-97%), 100%, and 75% (95% CI, 13%-96%), respectively, and the probability of overall survival (OS) was 98% (95% CI, 95%-100%), 100% (95% CI, 43%-98%), and 75% (95% CI, 13%-96%), respectively. No statistical difference was observed between the patients with classic cytogenetic findings and those with additional chromosomal abnormalities in terms of PFS and OS. CONCLUSIONS: In contrast to adults with CML, additional chromosomal abnormalities observed at diagnosis do not seem to have a significant prognostic impact

Chronic Myeloid Leukemia in Children: Immune Function and Vaccinations

Children with CML need TKI treatment for many years, and the lack of knowledge about immune dysfunction with TKI has hindered routine immunizations. This review attempts to provide an overview of the effects of TKIs licensed for children (e.g., imatinib, dasatinib, and nilotinib) on immune function, as well as its implications on immunizations. We discuss surveillance strategies (e.g., immunoglobulin blood serum levels and hepatitis B reactivation) and immunizations. All inactivated vaccines (e.g., influenza, pneumococcal, and streptococcal) can be given during the treatment of CML in the chronic phase, although their efficacy may be lower. As shown in single cases of children and adults with CML, live vaccines (e.g., varicella, measles, mumps, rubella, and yellow fever) may be administered under defined circumstances with great precautions. We also highlight important aspects of COVID-19 in this patient population (e.g., the outcome of COVID-19 infection in adults with CML and in children with varying hemato-oncological diseases) and discuss the highly dynamic field of presently available different vaccination options. In conclusion, TKI treatment for CML causes humoral and cellular immune dysfunction, which is mild in most patients, and thus infectious complications are rare. Routine immunizations are important for health maintenance of children, but vaccinations for children with CML on TKI therapy should be carefully considered