The survival rate of CP-CML patients is close to that of the general population; however, CP-CML patients with concurrent T315I mutations have a poorer prognosis. In the imatinib era, the median OS of CP-CML patients with the T315I mutation was found to be 22.4 months15. In the ponatinib era, the 5-year survival rate for CP-CML patients with the T315I mutation was 70%9. Currently, treatment options for patients with the T315I mutation primarily include third-generation TKIs (such as ponatinib, asciminib, and olverembatinib) and allogeneic hematopoietic stem cell transplantation (HSCT).5 Research indicates that in CP-CML patients with the T315I mutation, ponatinib is superior to allogeneic HSCT16. Typically, the timing for detecting BCR::ABL1 KD mutations is based on increasing levels of BCR::ABL1 transcripts7, but low-level T315I mutations often occur before clinical detection17, Therefore, timely identification of patients with the T315I mutation can help physicians implement appropriate interventions to improve disease prognosis.
Several studies have explored the relevant factors and predictive models for molecular response, TKI resistance, and treatment failure in CML patients18–20. However, a model for predicting the T315I mutation in CP-CML patients has yet to be developed. Here, we developed an innovative and meaningful nomogram model for evaluating the risk of T315I mutation in CP-CML patients. We included 1,466 eligible CP-CML patients from 24 hematology centers. The incidence of the T315I mutation was 2.0%, similar to the 4.2% incidence reported in a recent study9. From the training cohort of 1,466 patients, we identified five independent risk factors influencing the occurrence of the T315I mutation in CP-CML patients: PBB, ACA, choice of dasatinib as a TKI, non-EMR at 3 months, and BCR::ABLIS > 1% at 6 months. We developed a nomogram model based on these factors to predict the 5-year, 10-year, and 15-year T315I-free survival probabilities. The model was validated with 820 patients from an additional 20 hospitals and demonstrated good discrimination, accuracy, and clinical net benefit. In addition, the nomogram effectively stratified patients into low-risk and high-risk categories, showing valuable clinical applicability.
This study revealed that the percentage of PBB was a predictor of the occurrence of the T315I mutation in CP-CML patients. An increased percentage of PBB indicates disease progression and is associated with higher grades of bone marrow fibrosis and difficulty in achieving treatment-free remission21. The incidence of ACA in CP-CML patients has been found to be approximately 5%22, similar to the findings of our study. ACAs are categorized into major and minor routes and have been shown to negatively affect survival and prognosis13. A German study revealed that ACA is common in the T315I mutation subtype, with the 3q26.2 rearrangement highly correlated with BCR::ABL1 mutations23. Patients with genetically unstable CML are more likely to develop KD mutations, possibly related to changes in the DNA damage response, cell cycle checkpoints, and DNA repair24,25. In CP-CML patients with the T315I mutation treated with ≥ 1 TKI, baseline data revealed that 73.3% of patients used dasatinib, whereas 4.4–57.8% of patients used other TKIs26. The 2-year follow-up of the DASISION study revealed that among patients with BCR::ABL mutations in the dasatinib group, 70% had the T315I mutation, whereas no T315I mutation was found in the imatinib group27. Our results are consistent with these findings, suggesting that a history of dasatinib use predicts a greater likelihood of the T315I mutation. Therefore, monitoring for the occurrence of the T315I mutation in patients currently using or who have previously used dasatinib is crucial. EMR has become an effective predictor of long-term progression-free survival (PFS) and OS4. Studies have shown that adjusting early intervention strategies on the basis of EMR at 3 months can be beneficial28. A BCR::ABL1IS ≤ 1% at 6 months is also a recognized predictor of long-term survival29. In the IRIS study, the estimated 6-year PFS rate for patients with a BCR::ABL1IS ≤ 1% at 6 months was 97%, whereas it was 80% for those with a BCR::ABL1IS > 1% at 6 months. This finding supports the rationale that failure to achieve a molecular response is associated with the T315I mutation.
Additional mutations other than BCR::ABL1 KD mutations are gaining increasing attention. A position paper recommended the use of next-generation sequencing (NGS) for mutation detection in CP-CML patients experiencing "failure" in first- or second-line TKI treatment30. Compared with Sanger sequencing, NGS can detect the T315I mutation three months earlier and identify mutations undetectable by Sanger sequencing31. In CML patients, the presence of epigenetic gene mutations at diagnosis, such as ASXL1, IKZF1, BCOR, TET1/2, IDH1/2, DNMT3A/3B, and EZH2, is associated with lower molecular response rates and reduced PFS7,32,33. A novel HDAC I/IIb inhibitor has been shown to prevent T315I-induced CML progression and target leukemia stem cells (LSCs) responsible for CML relapse by inhibiting EZH234. ROS-induced oxidative DNA damage in LSCs can lead to the T315I mutation and IKZF1 deletion. Studies on the correlation between non-BCR::ABL1 KD mutations and T315I mutations are limited. We anticipate incorporating parameters related to gene mutations into our model in future research.
Our study has certain limitations. First, as a retrospective study, it inevitably has some degree of internal bias. Second, given the complexity of clinical situations, we did not strictly screen patients on the basis of the different first-line TKIs used or the various TKI switch scenarios, which may have reduced the model's accuracy but also increased its applicability. And it does not Impede the model’s ability to identify patients who require close monitoring.