To the editor
Durable achievement of treatment-free remission (TFR) after tyrosine kinase inhibitors (TKIs) is one therapeutic goal for patients with chronic phase chronic myeloid leukemia (CML-CP). Although several studies revealed the prognostic factors for TFR, few consistent results were reported because it has not been investigated comprehensively and heterogeneity among patient characteristics [1–3]. Several reports demonstrated that antitumor immune responses can suppress CML cells with positive clinical impacts, thus antitumor immunity has important role in patients with CML-CP [4].
We previously reported that human leukocyte antigen (HLA) polymorphisms are associated with the successful achievement of TFR in patients with CML-CP [5]. The report showed the results from 33 patients who discontinued tyrosine kinase inhibitors (TKIs). We further evaluated 16 patients, investigating a total of 49 patients. The median age was 62 (interquartile range [IQR]: 55–71) years; 28 patients were male; and 26, 16, and 7 patients had low, intermediate, and high Sokal risk scores, respectively. The front‐line TKI was imatinib in 20 cases and second-generation TKIs (dasatinib or nilotinib) in 29; the TKI used before discontinuation was imatinib in 8 cases and second generation TKIs in 41. The median TKI treatment duration and duration of the deep molecular response (DMR) time were 55.8 (IQR: 40.9–87.8) months and 32.9 (IQR: 27.7–42.8) months, respectively (Table S1). Additionally, 26 achieved TFR [52.3% (95% confidence interval; CI: 37.4–65.2)] at one year, and the median follow‐up time for those in the TFR phase was 56.7 (IQR: 36.1–70.4) months. Although the previous report demonstrated that male sex was a favorable prognostic factor for TFR, univariate analysis of the clinical characteristics for TFR (including age, sex, Sokal-risk score, use of first-line TKIs, TKI used before discontinuation, DMR time before TKI discontinuation and duration of TKI treatment) identified no significant prognostic variable for a lower likelihood of molecular relapse (Table S2). Univariate analysis of killer immunoglobulin-like receptor (KIR) and HLA profiles revealed that KIR genotype, KIR allele type, KIR and HLA licensing status, KIR3DL1 and HLA-Bw interaction avidity and HLA-C as described previously did not affect the incidence of molecular relapse (Table S3). In contrast, lacking HLA-A*02:01, *24:02, or *11:01 alleles were worse prognostic factors for TFR (HR, 2.493; 95% CI, 1.047–5.931, p = 0.039). Multivariate analysis identified HLA-A profile as an independent prognostic factor for TFR in patients with CML-CP (HR, 2.874; 95%CI, 1.170–7.062; p = 0.021) (Table 1). These results of further analysis of additional patients suggested that HLA polymorphisms are associated with the successful achievement of TFR in patients with CML-CP, and T-cell–mediated adaptive immunity is important for TFR. Hence, we further investigated the detection of neoepitope that elicits HLA-restricted T-cell immune response to CML.
Table 1.
Multivariate analysis revealed HLAs polymorphisms are associated with molecular relapse after TKI discontinuation
| N | Hazard ratio | 95% CI | P value | |
|---|---|---|---|---|
| HLA-A*02:01, 11:01, 24:02 | ||||
| Positive | 38 | 1 | ||
| Negative | 11 | 2.874 | 1.170–7.062 | 0.021 |
| Sex | ||||
| Female | 21 | 1 | ||
| Male | 28 | 0.643 | 0.294–1.586 | 0.375 |
| TKI treatment duration before discontinuation | ||||
| < 55.8 months | 24 | 1 | ||
| ≥ 55.8 months | 25 | 1.373 | 0.517–3.639 | 0.524 |
| DMR duration | ||||
| < 32.9 months | 24 | 1 | ||
| ≥ 32.9 months | 25 | 0.454 | 0.166–1.246 | 0.125 |
Supplementary Information
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Funding
SK reports grants and personal fees from Bristol-Myers Squibb, Pfizer, and Novartis Pharmaceuticals outside the submitted work.
Declarations
Conflict of interest
All authors declare that they have no conflict of interest.
Ethical Approval
This study was approved by the institutional review board of Saga University (UMIN-CTR, ID: R000020356).
Informed Consent
Written informed consent was obtained from all patients before registration, as required by the Declaration of Helsinki.
Footnotes
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References
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