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Santiago et al. J Transl Genet Genom 2021;5:380-95 https://dx.doi.org/10.20517/jtgg.2021.16 Page 388

pediatric ALL, had a dismal outcome. Despite high-intensity chemotherapy followed by allogenic
hematopoietic stem cell transplantation (HSCT) intensification in first complete remission, less than 50% of
[74]
the patients were long-term survivors . Following the remarkable clinical efficacy of the BCR-ABL TKI,
+
[8]
imatinib, in chronic myeloid leukemia, TKI became a therapeutic opportunity for Ph ALL . Clinical trials
from the COG and the European EsPhALL consortia have demonstrated a robust survival benefit in Ph
+
ALL with the incorporation of imatinib combined to an intensive chemotherapy backbone, thus challenging
the indication of HSCT in first remission in the TKI era. With imatinib-based regimens, almost 70% of Ph +
ALL patients can avoid HSCT and achieve durable remissions [75-78] . The second generation BCR-ABL1 TKI,
dasatinib, is an alternative to imatinib in combination to intensive chemotherapy that has been tested in
COG and EsPhALL non-randomized clinical trials. In these studies, dasatinib did not contribute to further
improve the clinical outcome, showing a similar efficacy to historical imatinib-based regimens [79,80] .
However, earlier introduction of protracted TKI administration by mid-induction appears to increase the
achievement of post-induction MRD negativity, then reducing the need of HSCT consolidation in first
remission. The Chinese Children’s Cancer Group (CCCG) ALL-2015 phase 3 randomized trial compared
the combination of either dasatinib or imatinib to the St. Jude Total Therapy chemotherapy backbone and
suggested dasatinib’s superiority over imatinib with regards to EFS and OS. This result needs to be
confirmed as the median follow-up remains relatively short. In addition, the outcomes in the imatinib arm
were unexpectedly inferior compared to those of prior imatinib-based regimens in COG or EsPhALL trials
and the TKI dosage used was different than prior studies . The promising success of TKI and
[81]
chemotherapy combination in the treatment of Ph ALL has established a new treatment paradigm for ALL
+
in the molecular era, nourishing the hope of new therapeutic opportunities by targeting novel oncogenic
drivers in ALL. Recently, the combination of TKI and immunotherapy further expands the precision
medicine paradigm in Ph ALL. The chemotherapy-free phase 2 D-ALBA study demonstrated early
+
+
promising results in adults with newly-diagnosed Ph ALL. The treatment consists of 85-day induction
phase combining dasatinib and glucocorticoids followed by a consolidation with 2 cycles or more of the
CD3/CD19 bi-specific antibody, blinatumomab, in association with dasatinib. Interestingly, after induction
therapy with dasatinib and glucocorticoids only, 98% of the patients achieved a complete response, and 29%
a molecular response. After 2 cycles of blinatumomab and dasatinib consolidation, the molecular response
[82]
rate exceeded 60% .

Ph-like ALL
The clinical and biologic similarities between Ph-like ALL and Ph ALL provide the rationale to model
+
tailored TKI-based therapy in Ph-like ALL with an anticipated efficacy similar to that observed in Ph ALL.
+
In vitro and in vivo evidence have reinforced the putative sensitivity of Ph-like ALL to selected TKIs by
demonstrating activity of ABL inhibitors, imatinib or dasatinib, and JAK inhibitor, ruxolitinib, for those
harboring ABL-class fusions and JAK-STAT pathway mutations, respectively [19,20,83-85] . There is a growing
body of clinical evidence from case reports or small patient series to confirm the preclinical efficacy of ABL
and JAK inhibitors in Ph-like ALL [86-88] . Preclinical and clinical reports have also demonstrated the
sensitivity of NTRK inhibitor, larotrectinib, or ALK inhibitor, crizotinib, for the rare ETV6-NTRK3 Ph-like
ALL [19,89,90] . Recently, mutations conferring resistance to imatinib and dasatinib have been identified in
relapsed EBF1-PDGFRB Ph-like ALL, raising the necessity to monitor kinase domain mutations over the
course of therapy to guide TKI selection . Thanks to the progress in genomic characterization of ALL, Ph-
[91]
like ALL has become a new paradigm of tailored precision medicine, but prospective clinical trials are much
needed to confirm the benefit of TKI and chemotherapy in Ph-like ALL. Several ongoing clinical trials
should shortly answer some of these urgent questions [Total XVII (NCT03117751); AALL1131
(NCT01406756); AALL1521 (NCT02723994)] [Table 1].