High-Risk “Failure” Events Predicting Worse Survival in Patients with Chronic Myeloid Leukemia during Tyrosine Kinase Inhibitor Therapy

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Background Meeting “failure” milestones as defined by the ELN2020 recommendations predicts poor outcomes in CML patients on TKI therapy. However, there are limited data exploring which “failure” events are the high-risk indicators that most significantly impact survival in patients with CML. Aims To identify which “failure” events during TKI-therapy are more robust and important predictors of survival in CML. Methods Data from consecutive adults with newly-diagnosed CML-CP receiving initial TKI therapy and regular monitoring at Peking University People's Hospital were interrogated. In this study, the “failure” events of interest were defined by the ELN 2020 recommendations. Survival was calculated using the Kaplan-Meier method with the log-rank test. The X-tile software was used to determine optimal cut-off values of continuous co-variates for predicting survival which could visualize the best cut-points for creating such divisions by calculating at each division by a variety of standard statistical tests, including the log-rank test for survival and means tests and so on. Cox regression models were used for uni- and multi-variable analyses to identify co-variates associated with survival. Results A total of 2,092 patients were enrolled in this study. 1,359 (65%) patients were male. Median age was 42 years (IQR: 36-58). 1,109 (53%), 502 (24%) and 230 (11%) patients were identified as ELTS low-, intermediate- and high-risk, respectively. 251 (12%) patients had unknown ELTS score. 1,632 (78%) patients received initial imatinib therapy; 460 (22%), 2G-TKI therapy (nilotinib, n = 313; dasatinib, n = 78; flumatinib, n = 69). Median follow-up was 60 months (IQR: 33-94 months). At the last follow-up, 16 patients did not achieve CHR by 3 months. 202 patients experienced BCR::ABL transcript level >10% at 3 months and confirmed within 1-3 months; 100 patients, >10% at 6 months; 50 patients, >10% at 12 months; 55 patients, >1% at 12 months; 186 patients, detected TKI-resistant ABL mutation; 68 patients, harbored Ph+ ACAs; 15, 38 and 136 patients, loss of CCyR, MMR and CHR alone or combined at the first episode of failure events occurred. Kaplan-Meier analyses showed that patients with BCR::ABL transcript levels >10% at 3, 6, or 12 months, >1% at 12 months, loss of MMR and detected ABL mutations had the similar outcome to those with no failure event occurred (all p values > 0.2), but significantly superior than those with no CHR by 3 months, loss of CHR or CCyR, or harboring Ph+ ACA (p = 0.001-0.03). Moreover, there were no significant differences in survival among the patients who failed to achieve CHR by 3 months, lost CHR or CCyR, or harbored Ph+ ACA (p = 0.69). Multi-variable Cox analyses further confirmed these results. Therefore, we defined these four events as high-risk “failure” events on TKI therapy. In patients with the high-risk “failure” events, multi-variable Cox analyses were further performed to identify co-variates associated with worse survival. The analyses revealed that the 2G- or 3G-TKI used, HB < 110 g/L, PLT < 35×109/L, blasts in PB or BM ≥10%, and blood basophils < 5% were significantly-associated with worse survival. Based on the number of adverse prognostic co-variates, patients were classified into low- (0-1 co-variate, n = 95, 59%), intermediate- (2-3 co-variates, n = 49, 30%) and high-risk (4-5 co-variates, n = 17, 11%) groups with significant different outcome (2-year survival rates: 96% [95%CI: 93-99%] versus 56% [48-64%] versus 17% [9-25%], p < 0.001). Conclusions Failure to achieve CHR by 3 months, loss of CHR or CCyR and the emergence of Ph+ ACA are robust predictors of worse survival in patients with CML during TKI-therapy. In patients with the high-risk “failure” events, certain clinical co-variates such as the 2G- or 3G-TKI used, the lower HB, PLT and blood basophils, and the higher blasts can further predict the worse survival. These insights emphasize the need for vigilant monitoring the patients with high-risk “failure” events to implement tailored treatment strategies.

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