HLAPolymorphisms Are Associated with Treatment-Free Remission Following Discontinuation of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

Abstract

Treatment-free remission (TFR) is one of the therapeutic goals for patients with chronic phase chronic myeloid leukemia (CML-CP). Although previous reports indicated that antitumor immunity contributes to TFR, its determinants are still unclear. We previously reported that allelic polymorphisms of killer immunoglobulin-like receptors (KIR) and human leukocyte antigens (HLA) are associated with achievement of deep molecular response (DMR) in patients with CML-CP. Here, we examined the association between TFR and polymorphisms of KIRs and HLAs in patients who discontinued tyrosine kinase inhibitors (TKI). Seventy-six patients were enrolled, and their KIR and HLA polymorphisms and natural killer (NK) cell activation status were investigated as previously described.Overall, 33 patients discontinued TKIs, and 21 of 33 achieved TFR [63.6%; 95% confidence interval (CI), 44.9%-77.5%] at 1 year. Multivariate analysis revealed that male sex (HR, 0.157; 95% CI, 0.031-0.804; P ¼ 0.003) and HLA-A à 02:01, à 11:01, or à 24:02 (HR, 6.386; 95% CI, 1.701-23.980; P ¼ 0.006) were associated with TFR. Patients who achieved DMR and discontinued TKIs exhibited higher NK cell activation status than those who did not. By contrast, there were no significant differences in NK cell activation status between the patients who achieved TFR and those who experienced molecular relapse. These results suggest NK cell activation status contributes to achievement of DMR, whereas T-cell-mediated immunity contributes to TFR in patients with CML-CP.

Subsequent attempt tyrosine kinase inhibitor discontinuation in patients with chronic myeloid leukemia; a single institute experience

“…DMR was defined as MR 4.0 or a deeper response, and molecular relapse was defined as loss of the DMR at two consecutive time points or loss of the MMR at a single time point. The TMA method for quantification of BCR‐ABL1 transcripts was the only method approved by the national insurance body of Japan until June 2015, and before the implementation of the IS at Saga University 8 . The TMA method was used only to confirm DMR before TKI discontinuation.…”

“…The TMA method for quantification of BCR-ABL1 transcripts was the only method approved by the national insurance body of Japan until June 2015, and before the implementation of the IS at Saga University. 8 The TMA method was used only to confirm DMR before TKI discontinuation. Monitoring after TKI discontinuation was assessed by RQ-PCR using the IS.…”

Treatment-free remission and immunity in chronic myeloid leukemia

“…The immune response in CML have not been fully elucidated comprehensively. We previously reported HLA polymorphisms associated with TFR, while NK cell activation status and KIR polymorphisms contributed to deep molecular DMR [15,25], thus we hypothesized DMR depends on NK cell activation status and T-cell-mediated immunity contributes to TFR in CML-CP patients.…”

“…Human leukocyte antigen (HLA)-restricted cytotoxic T cells (CTLs) induced by leukemia-associated antigens (e.g., BCR-ABL1, PR1, BMI-1, PRAME, WT1, or CXorf48) are detected in patients with CML, and patients with CXorf48-specific CTLs are more likely to achieve TFR following imatinib discontinuation than those without [14]. We previously showed that certain HLA alleles, which induce antigen-specific CTLs, are associated with the successful achievement of TFR in patients with CML-CP [15]. Increased numbers of the memory CD8 + T-cell (CD8 + CD27 + CD45RA − ) fraction in patients with CML-CP is associated with successfully maintaining TFR [16], while patients with increased PD-1-expression on CD8 + CTLs (a signature of immune cell exhaustion) are at increased risk of relapse [17].…”

Evolution of CML treatment

“…This is thought to be due to the immune system. Dr. Ureshino has been studying the importance of immunity in TFR at his institution and in multicenter trials [5].…”