Would you recommend adding a TKI to a pediatric regimen for a AYA B-ALL patient with IKZF1 mutation?

I would not add a TKI to standard chemotherapy in this situation.

Background/Rationale: IKZF1 mutations (specifically deletions) are associated with inferior prognosis. Specifically, the prognosis appears to be worst with mutations that lead to loss-of-function (e.g., focal deletions [Beldjord et al., PMID 24740809]) and/or when coupled with other genetic lesions such as deletions of PAX5 or CDKN2A/-B as in the so-called "IKZF1-plus" subtype (Stanulla, et al., PMID 29498923). However, there are no studies to date that show addition of targeted therapies can improve the outcome of these patients. In fact, there are no available agents that target the Ikaros protein (the gene product of IKZF1).

That being said, there is some correlation between IKZF1 mutations and the Philadelphia chromosome (Ph)-like or BCR::ABL1-like subgroup of B-ALL (Mullighan et al., PMID 19129520). However, the way that Ph-like ALL is recognized is generally through the identification of specific mutations (most often gene fusions) that involve a signal-transduction kinase like ABL1, JAK2, or CRLF2. When these genetic abnormalities are identified, it is appealing to consider the impact that targeted agents could have in these cases. There are ongoing prospective studies exploring this very question (e.g., COG AALL1521, NCT02723994), and there are some small series demonstrating activity when these targeted agents are used (e.g., Tanasi et al., PMID 31434701). In my opinion, though, the evidence available at this time does not support the routine use of these agents as part of a front-line treatment strategy.

So for now, IKZF1 mutations are prognostic but not predictive.