The stepbrothers of ABLSON have their own sensitivity

In this issue of Blood, van Outersterp et al investigate the differential sensitivity to tyrosine kinase inhibitors (TKIs) of Abelson kinase-class (ABL-class) acute lymphoblastic leukemia (ALL).¹ ABL-class ALL is part of the Philadelphia chromosome (Ph)–like or BCR::ABL1-like ALL, initially defined by gene expression studies showing a subset of B-cell ALL (B-ALL) with an expression profile similar to Ph⁺ ALL, but with fusions of ABL-class tyrosine kinase genes other than BCR::ABL1.² 

The use of TKIs (first imatinib, followed by second- and third-generation TKIs) in combination with conventional chemotherapy in children and young adults, or with reduced intensity in young and older patients, resulted in a dramatic improvement in overall survival compared with chemotherapy alone in Ph⁺ ALL.^3,4 

Individual case reports were first published showing that ABL-class ALL, not accurately diagnosed and treated as Ph-negative B-ALL, was sensitive to imatinib at relapse or in the refractory setting. Several groups then developed algorithms to detect and characterize Ph-like ALL with the logical aim of identifying this subset of patients who frequently respond poorly to chemotherapy and to add a TKI to their conventional chemotherapeutic regimens. Despite the many partner genes, including ABL1-, ABL2-, PDGFRB-, and CSF1R-fused ALL, the choice of TKI was empirical. However, from the beginning of the development of TKIs, the kinome profile of each compound was well defined, and their respective potency was expressed as the half-maximal inhibitory concentration (IC₅₀).

The study of van Outersterp et al provides a comprehensive assessment of ABL-class leukemic samples from pediatric patients enrolled in clinical trials conducted in the Netherlands, Germany, and the United States. Sensitivity to imatinib, dasatinib, and bosutinib was assessed ex vivo in primary samples, samples from patient derived xenografts (PDX) -expanded ALL, and Ba/F3-transduced cells and was compared with BCR::ABL1-positive ALL cases. As reported by the authors, the PDGFRB fusion gene was most common, followed by ABL1, CSF1R, and ABL2. The conclusions of the study were not intuitive. Sensitivity to imatinib, dasatinib, or bosutinib was not determined by the 5’ fusion partner, the presence of additional mutations (IKZF1, PAX5, or CDKN2A/B), the ALL immunophenotype, or the presence or absence of an Src homology 3 (SH3) domain in the fusion protein but by the ABL-class fusion gene. Imatinib exhibits potency against all fusions, with IC₅₀ values ranging from 1.6 to 0.07 μM against ABL2, ABL1, CSF1R, and PDGFRB fusion proteins, in concordance with the C_trough plasma concentration achieved with imatinib in vivo. By contrast, dasatinib, although efficient against ABL2, ABL1, and CSF1R fusions, was less potent against PDGFRB fusion. Bosutinib, a more selective TKI against the BCR::ABL1 kinase, was only active against ABL2 and ABL1 fusions.¹ 

As stated by the authors, these results should be considered when combining a TKI with chemotherapy for the treatment of ABL-class ALL, because most of the studies in children are using imatinib or dasatinib. However, can we translate these conclusions in the adult ALL setting?

The sensitivity of adult ABL-class ALL is superimposable onto that of children. However, the current therapeutic strategy in Ph⁺ ALL in adults is now based on ponatinib in combination with low-intensity chemotherapy or chemotherapy-free regimens.^5,6 Alongside the inhibition of ABL kinase (IC₅₀ = 0.3 nM), the main property of ponatinib is to maintain activity against the ABL-T315I mutant frequently associated with Ph⁺ ALL relapse or refractoriness.

Using the kinase hot spot assay, consisting of a direct measurement of the substrate phosphorylation, O’Hare et al were able to profile ponatinib against >100 tyrosine kinases. IC₅₀ against PDGFRB was reported to be 7.7 nM (target C_trough plasma concentration, 23 nM). Activity against CSF1R was not mentioned.⁷ These observations could be a warning for future trials testing ponatinib in BCR::ABL1-like ALL in adults. Therefore, a study mirroring the report by van Outersterp et al and including ponatinib would be extremely useful.

Conflict-of-interest disclosure: P.R. declares no competing financial interests.