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Targeted therapy for pediatric BCR-ABL1-like ALL
which used imatinib (300 mg/m2). A very recent study,
where dasatinib was used at a higher dose (80 mg/m2) and
randomized versus imatinib (300 mg/m2), showed a superi-
ority of dasatinib; however, follow up of this study was rel-
atively short, and results in the cohort treated with imatinib
were inferior to those obtained by the EsPhALL and COG
groups with the use of imatinib, thus, challenging the evi-
dence of superiority itself. Other TKI such as nilotinib,
bosutinib and ponatinib are still being investigated as phase
I and II trials in pediatric cancers. At this moment, the
choice of both imatinib or dasatinib appears to be reason-
able as TKI in frontline ALL protocols for children and ado- lescents.7,9,10,67,68
In summary, there are still some challenges to implant- ing targeted therapy into frontline ALL treatment. There is a need for an early identification of BCP-ALL harboring ABL-class and JAK-pathway alterations to allow prompt intervention with targeted therapy to reduce intensity of chemotherapy, and refine HSCT indications, as already shown for Ph+ ALL.5-10 Diagnostic technologies such as RNA sequencing and similar strategies should be imple- mented in a timely fashion for all “B-other ALL”.
Although ABL-class and JAK-pathway alterations account for most BCR-ABL1-like ALL cases, there are also several alterations involving kinases that are not inhibited by either TKI or JAK inhibitors. Future studies are required to assess the potential of targeted inhibitors of these kinases in model systems and human leukemic cells. In the meantime, for this subgroup of BCR-ABL1-like cases without known targetable lesions, the optimal treatment should be based on MRD response, and might include innovative therapies such as immunotherapy. Moreover, all ALL patients treated with targeted approaches should be registered and closely followed up on the molecular level as recently discussed by Elitzur and Izraeli in order to understand response and resistance to targeted treat- ment.69 Due to the rarity of these clinical entities, collab- orative international efforts are strongly needed to con- duct successful studies.
Acknowledgments
The authors would like to thank AIRC 2017 20564; CRUK/AIRC/FC AECC 22791 and AIRC Molecular Clinical Oncology 5 per mille 21147.
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