**5. Conclusions**

The therapeutic approach to CML has changed since the introduction of the TKI imatinib, followed by dasatinib, nilotinib, which was approved for use in children, and ponatinib, which became the first-line treatment in adults and expanded the therapeutic options, pushing allogeneic stem cell transplantation to a third-line treatment for most pediatric cases. Unfortunately, the selection of a TKI continues to rely on clinical experience in adults [108] without sufficient data on efficacy and safety specific to pediatric patients.

The availability of three TKIs is challenging to choose a first-line option, but it also gives clinicians additional treatment chances in case of a suboptimal response [108].

More experience has been gained about efficacy, toxicity profiles, and comorbidities of Imatinib compared to the other TKIs [22,37,109]. The appearance of resistance or intolerance phenomena has required the development of a second generation of TKI. Drug availability, ease of administration, and financial issues should also be considered.

Evidence-based recommendations have been established for treating CML in adults treated with TKIs. Appropriate guidelines are, however, difficult to extend to pediatric patients given the very rare occurrence in children and adolescents [105]. As a matter of fact, the CML incidence increases with age, from 0.09/100,000 at ≤ 15 years of age to 7.88/100,000 at ≥ 75 years of age. Needless to say, here 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 of pediatric patients.

TKIs are designed to inhibit BCR-ABL1 kinase, but they have unfavorable effects, so-called "off-target" complications, such as growth impairment, especially important in children, because they are constantly and actively growing. Long-term morbidity due to TKIs 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 managemen<sup>t</sup> 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 [110].

Limited experience with very young children, the transition of teenagers to adult medicine, and the goal of achieving treatment-free remission for this rare leukemia are more significant obstacles that require further clinical investigations [48,108].

Lastly, in order to carry out a possible and viable therapy with TKIs in the pediatric age, a key role is played by developing appropriate formulations specifically customized toward this kind of patients, since these drugs are often available in solid dosage forms, which are difficult to administer in children.

**Funding:** Authors acknowledge Project POR Puglia FESR-FSE 2014–2020 Azione 1.6. Innonetwork progetto D.I.V.A., cod. JD6EDJ7 and the University of Bari "Aldo Moro" (Italy) for their financial support.

**Conflicts of Interest:** The authors declare no conflict of interest.
