Secondary lesions and sensitivity to signaling inhibitors in iAMP21 acute lymphoblastic leukemia

Abstract

Intrachromosomal amplification of chromosome 21 (iAMP21) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in children is a high-risk subtype for which targeted drugs are lacking. In this study, we determined the frequency of secondary lesions in 28 iAMP21 BCP-ALL patient samples and investigated cellular sensitivity for candidate-targeted drugs. iAMP21 was enriched in FLT3 aberrations (10.7% vs. 50.0%, p = 0.003) and SH2B3 inactivation (7.14% vs. 46.4%, p = 0.002), compared with 28 B-other cases, and these alterations co-occurred in 21.4%. The occurrence of lesions in CRLF2 and IL7R was similar between iAMP21 and B-other cases (25% vs. 17.9%, p = 0.746 and 7.14% vs. 0%, p = 0.491 respectively) as were mutations in JAK1 and JAK2 (3.57% vs. 0% and 10.7% vs. 10.7%, p = 1 for both). Sensitivity to the FLT3 inhibitor gilteritinib did not differ between iAMP21 and B-other cases irrespective of FLT3 status. However, iAMP21 samples harboring both FLT3-ITD and SH2B3 lesions showed the highest sensitivity. CRLF2-rearranged iAMP21 samples were slightly more sensitive to JAK inhibitor ruxolitinib than those without, although a lack of sensitivity was present in 50% of iAMP21 cases. Trametinib sensitivity varied among iAMP21 samples with over half of iAMP21 samples being sensitive irrespective of RAS-pathway mutation status or other secondary lesions. In summary, iAMP21 leukemias were enriched in FLT3 and in SH2B3 lesions, which when co-occurring affected sensitivity to FLT3 inhibition by gilteritinib but not JAK inhibition by ruxolitinib. Together, our results suggest that FLT3 and RAS signaling inhibitors are of interest for further (pre)clinical evaluation in iAMP21 BCP-ALL.