CO63 | abcg2 and havcr2 SPNs are associated with long-term TFR maintenance in chronic myeloid leukemia patients

Abstract

Background: The new clinical goal for patients with chronic-phase Chronic Myeloid Leukemia (CML) is treatment-free remission (TFR). Currently, no validated predictive biomarker can determine the probability of TFR success. Among the most intriguing are ABC proteins, including ABCG2, membrane transporters implicated in drug resistance, and immune checkpoints, including TIM-3 (encoded by the HAVCR2 gene), regulators of suppressive pathways.
Aim: To investigate the role of ABC proteins and immune checkpoints genetic polymorphisms in predicting TFR maintenance.
Methods: Among 108 CP-CML patients (median age 66 years, range 29-92), who discontinued TKI therapy (61% imatinib, 26% nilotinib and 13% dasatinib) followed by Hematology Divisions of Udine, Pordenone and Trieste, we analyzed four ABCB1 (rs1045642, rs2032582, rs1128503, rs3213619), two ABCG2 (rs2231137 and rs2231142), five PDCD1 (rs36084323, rs11568821, rs2227981, rs10204525, rs7421861), two CTLA4 (rs231775 and rs3087243), and two HAVCR2 (rs1036199 and rs10515746) polymorphisms, as well as the LAG3 rs870849 polymorphism. We compared TFR rates across different genotypes. Statistical analyses were performed using the Cochran-Armitage trend test under an additive model with the number of minor alleles (0, 1, or 2) as the predictor, survival analysis was conducted using the log-rank (Mantel-Cox) test.
Results: Overall, 68% of patients maintained TFR, whereas 32% resumed TKI therapy after a median of 4 months (range 0–36). Among the analyzed SNPs, a significant association was observed between the G allele of the ABCG2 rs2231137 polymorphism and TFR maintenance (12 months TFR maintenance rate: GG=74%, GA=64%, AA=0%, p=0.027). Similarly, the minor allele of both HAVCR2 polymorphisms showed comparable associations: the C allele of rs1036199 (12 months TFR maintenance rate: AA=66%, AC=82%, CC=100%, p=0.023), and the A allele of rs10515746 (12 months TFR maintenance rate: CC=65%, CA=83%, AA=100%, p=0.017). These results were further supported by log-rank survival analysis based on genotype distribution for TFR maintenance, which confirmed the significance of each variant (p=0.0038 for ABCG2 rs2231137, p=0.038 for the HAVCR2 rs1036199, and p=0.025 for HAVCR2 rs10515746, respectively). Moreover, the two HAVCR2 SNPs are in linkage disequilibrium.
By combining the two most significant SNPs, a composite score was: +2 points were assigned for each A allele of ABCG2 rs2231137, and +1 point for each A allele of HAVCR2 rs10515746. This score demonstrated statistical significance in both logistic regression analysis (p=0.035) and log-rank survival analysis (p=0.0058) (FIG.1), supporting its potential utility as a predictive marker for TFR outcome.
Conclusions: Despite the relatively small sample size, our findings suggest that ABCG2 and HAVCR2 genotypes may influence their respective roles as a drug transporter and immune checkpoint, potentially affecting the ability to maintain TFR after TKI discontinuation.