Discovery of an Inherited Variant Associated with Susceptibility to Secondary Acute Lymphoblastic Leukemia (ALL) after Lenalidomide Maintenance and Autologous HCT for Multiple Myeloma (MM)

An increased risk of ALL second primary malignancy (SPM) has been observed with lenalidomide maintenance therapy after autologous HCT (len-post-autoHCT) for MM. Lenalidomide exerts its therapeutic effects via cereblon-mediated downregulation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). Inherited susceptibility variants in IKZF1 have been described for de novo ALL. We performed a case-control germline targeted sequencing study of the entire IKZF1 and IKZF3 genes with mean coverage ∼2,200X to investigate inherited susceptibility to ALL SPM risk. All cases and controls had a primary diagnosis of MM and received len-post-autoHCT with melphalan; sequencing was performed on an aliquot of the apheresis product or peripheral blood sample that was collected before autoHCT for MM. Cases of ALL SPMs were contributed by 4 individual centers and one national trial (BMT CTN 0702); each case had a maximum of 4 controls per case, sampled with replacement and matched on age, sex, race/ethnicity and duration of lenalidomide exposure (controls had longer duration of lenalidomide maintenance than cases). An additional control group of Acute Myeloid Leukemia/Myelodysplastic Syndrome (AML/MDS) SPMs after len-post-autoHCT were contributed by one center (Table). Multivariate logistic regression of case-control status, adjusted by age at HCT, sex, race/ethnicity, duration of lenalidomide maintenance, was performed for: 1) ALL SPM, 2) AML/MDS SPM, 3) ALL and AML/MDS SPM. We found the risk allele A of rs62447181 in IKZF1 had an OR=2.51 P=9.53 × 10−3 for ALL SPM, OR=4.18 P=0.09 for AML/MDS SPM and OR=2.57 P=4.98 × 10−3 for ALL&AML/MDS SPM. rs62447181 is a cis-expression quantitative trait loci (eQTL) of IKZF1 in blood (p=3.88 × 10−55 in eQTLGen Consortium data) and resides in a promoter-proximal enhancer predicted by the ENCODE project (Figure A). Our in silico analysis of transcription factor binding sites showed that rs62447181 disrupts the binding site of PLAGL2, a known AML oncoprotein (Figure B). Thus, we identified a germline variant, rs62447181, that may explain inherited risk of both ALL and AML/MDS SPMs. Gene-level analyses are on-going, and our findings should be validated in a larger independent dataset and in additional lenalidomide-containing MM regimens. Our results demonstrate an interesting risk variant for ALL, and potentially AML/MDS, SPM emerging in the setting of len-post-autoHCT. It is important to identify patients at higher risk of SPMs for survivorship screening, and to better understand the pathogenesis of acute leukemia SPMs associated with lenalidomide maintenance.