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Targeted therapy for pediatric BCR-ABL1-like ALL
ABL1-like cases harbor rearrangements of the cytokine receptor like factor 2 (CRLF2) resulting in upregulation of CRLF2 expression, in the vast majority as a consequence of either a translocation resulting in IGH-CRLF2 juxtaposition or a deletion of the PAR region of the X chromosome lead- ing to the P2RY8-CRLF2 fusion. Frequent concomitant acti- vating gene mutations occur in Janus kinases or other regu- lators of JAK-STAT signaling, with about 50% of CRLF2 rearranged cases presenting JAK1 or JAK2 point muta- tions.15,16,33,34 However, although the P2RY8-CRLF2 rearrangement is associated with an intermediate to poor outcome, its role with respect to relapse disposition is not fully clear, as the P2RY8-CRLF2 rearrangement has been reported in some cases to be lost at relapse, particularly when it has been identified initially in a sub-clone only.35-38 About one-third of BCR-ABL1-like non-CRLF2 rearranged ALL cases present chromosomal rearrangements that result in constitutive deregulation of a cytokine receptor or the formation of kinase fusion genes: a major subgroup includes ABL-class alterations involving ABL1, ABL2, CSF1R, LYN, PDGFRA and PDFGRB. A second major group regards rearrangements that activate JAK family kinases, including JAK2, EPOR, TYK2 and IL2RB. A third group con- stitutes a variety of other kinases or cytokine receptor alter- ations such as NTRK3, FLT3, FGFR1 and BLNK, and the RAS signaling pathway.11,13,23, 29,32-39
The limited data available confirm that BCR-ABL1-like ALL is associated with high-risk features also in pediatric patients. A single institution reported that the outcome in BCR-ABL1–like ALL patients, although inferior to that of other patients, was favorable with MRD-driven therapy and with the majority of patients treated in the higher risk arms and 15% undergoing HSCT.23,24 Subsequently, the COG found that, within standard risk ALL patients defined by National Cancer Institute (NCI) criteria, Ph-like ALL patients had a still good, but significantly lower, event-free- survival and no significant difference in survival when com- pared to non-Ph-like NCI standard risk ALL.40 In keeping with these data, Boer reported an increased cumulative inci- dence of relapse in BCR-ABL1–like ALL compared to non- BCR-ABL1–like B-other ALL.26 Finally, the AIEOP-BFM study group has recently reported the outcome of ABL-class fusion positive BCP-ALL in a retrospective study, which, although limited by its retrospective nature, and especially by a potential selection bias towards cases with a poor treatment response, indicates that these patients have an overall poor prognosis.41
The role of CRLF2 abnormalities on BCR-ABL1-like ALL outcome is still controversial. The COG showed that, while high CRLF2-expression predicted a dismal outcome in high-risk patients, the two specific genomic CRLF2-lesions did not confer independent prognostic significance.42 Similarly, CRLF2-rearrangements had no independent prog- nostic value in the Medical Research Council ALL97 trial,43 while the AIEOP-BFM study group reported that P2RY8- CRLF2 positive patients allocated in the non-HR group had a poorer prognosis.35,36 However, it should be remembered that data on CRLF2-rearranged BCP-ALL are not exclusive- ly restricted to cases with BCR-ABL1-like gene expression signature. Outcome data on BCR-ABL1-like ALL are sum- marized in Table 1. Overall, these data confirm that there is a clinical need for innovative targeted therapies which may be effective in this ALL subtype, as suggested by pre-clinical studies.
In vitro studies have, in fact, demonstrated constitutive
activation of kinase signaling networks in subsets of BCR- ABL1–like ALL harboring JAK pathway aberrations,42,44,45 and in vivo studies have demonstrated anti-leukemic activity of the type I JAK2 inhibitor ruxolitinib and of the dual PI3K/mTOR inhibitor gedatolisib given as a monotherapy in patient-derived xenograft models of JAK pathway– mutant BCR-ABL1-like ALL.44,46-50 Other studies have report- ed superior anti-leukemic efficacy with the type II JAK inhibitor CHZ868, which synergizes with dexamethasone to induce apoptosis, suggesting that type II JAK2 inhibition may be more effective to target CRLF2-rearranged BCP- ALL. This may be because type II inhibitors stabilize JAK2 in the inactive conformation, and overcome the JAK2 hyperphosphorylation observed with type I JAK inhibitors which target the ATP binding pocket and stabilize JAK2 in the active conformation.51 Likewise, pre-clinical experimen- tal studies have shown that cell lines and human cells expressing ABL-class fusions, as well as patient-derived xenograft models, have marked sensitivity to the TKI such as imatinib and dasatinib, similarly to BCR-ABL1 cells.52
Clinical studies are still very limited. A COG phase I trial (ADVL1011; clinicaltrials.gov identifier: 01164163) demon- strated the safety of JAK2 inhibitor ruxolitinib, given as monotherapy in children with relapsed or refractory can- cers,53 while anecdotal reports have provided evidence of efficacy of TKI (imatinib and dasatinib) to induce remission and clear MRD in patients with ABL-class fusions with poor response to previous chemotherapy.54-56
Optimal clinical management of pediatric BCR-ABL1-like ALL, thus, remains to be defined. The heterogeneous genomic landscape and the diverse array of targetable kinase-activating lesions of BCR-ABL1–like ALL require precise diagnostic strategies. Initially, the DCOG group used a validated Affymetrix gene expression array which included 110 probe sets, while the COG and SJCRH used an Affymetrix gene expression array with 255 probe sets to screen patients for BCR-ABL1-like ALL signature. Subsequently, COG first utilized a quantitative reverse transcriptase polymerase chain reaction (RT-PCR)-based low density array (LDA) platform to identify patients with BCR-ABL1-like ALL enrolled in their ALL COG front-line AALL1131 trial. As a second step, a series of multiplex RT- PCR assays, fluorescence in situ hybridization (FISH), and DNA sequencing to identify the underlying genomic aber- ration were applied.57,58 The COG is now using Archer tar- geted RNA sequencing instead of multiplex RT-PCR assays. Alternatively, combined FISH or targeted RNA-next gener- ation sequencing (NGS) strategies with probes capturing the recurrently fused genes can be successfully applied.59 In the future, NGS-based whole transcriptome sequencing should allow the detection of all relevant gene fusions and mutations in one step, as recently demonstrated by Gu et al.60 and Li et al.61 This approach will facilitate the timed diagnosis and the early implementation of specific treat- ments. Of note, despite the large number of individual kinase alterations identified, the majority converge on a limited number of pathways that can be targeted.
The best therapeutic strategy for this subgroup of patients remains a matter of investigation. Several ongoing studies are assessing the role of the addition of TKI or rux- olitinib on top of chemotherapy in pediatric BCP-ALL har- boring ABL-class fusions or CRLF2/JAK pathway alter- ations. In the current COG AALL1131 and AALL1521 (clin- icaltrials.gov identifier: 02883049 and 02723994, respectively) and SJCRH Total Therapy XVII trials (clinicaltrials.gov identi-
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