Response Adapted Dasatinib De-Escalation Strategy Compared to Upfront Low-Dose Dasatinib: A Prospective Cohort Study

The prognosis of chronic myeloid leukemia (CML) has improved with daily tyrosine kinase inhibitors (TKIs), allowing most patients to expect a normal life expectancy. However, TKI treatment is costly and has side effects (Bower H, 2016, Experts in CML, 2013, & Steegmann JL, 2016). This has raised interest among physicians and patients about whether the illness can be managed to allow treatment termination after a few years. The DESTINY trial reported that reducing the TKI dose to half for patients with stable MR3 or better appears safe and leads to fewer TKI-related adverse events (Clark, R.K., 2019). A recent prospective study found that at 12 months, patients in the de-escalation cohort had an 88.32% molecular recurrence-free survival rate (95% CI; 79%-98%) (Luo, J.,2022). This study aims to evaluate the safety of de-escalation, its association with fewer adverse events, and significant cost savings in TKI treatment for Indian patients.

This observational prospective cohort study included patients aged >18 years with BCR-ABL1 positive, treatment-naïve CML in the chronic phase. The de-escalation cohort started on dasatinib 100mg once daily. Patients who achieved BCR-ABL1 <10% at 3 or 6 months were de-escalated to half dose and closely monitored. The low-dose cohort started on dasatinib 50mg once daily from diagnosis. The primary endpoint was the proportion of patients who lose MMR on de-escalation and regain it on TKI resumption. The secondary objective was to compare upfront dasatinib 50mg with the de-escalated cohort.

We evaluated two cohorts: the dasatinib de-escalation group (N=65) and the low-dose dasatinib (50mg) group (N=63). Median age was 38.5 years (range 19–71) for the de-escalation group and 39 years (range 19–73) for the low-dose group. Male: Female ratio was 2.3:1 and 1.8:1, respectively. Median time since diagnosis was 6 days (range 0–22) for the de-escalation group and 7 days (range 0–58) for the low-dose group. ELTS risk scores for the de-escalation group were 58.5% low-risk, 27.7% intermediate-risk, and 13.8% high-risk. For low-dose group, the scores were 50.8% low-risk, 33.3% intermediate-risk, and 15.9% high-risk. The median total leukocyte count was 141 × 10^9/L (range 7.5–441) for the de-escalation group and 156.9 × 10^9/L (range 6.4–572.8) for the low-dose group. Median platelet count was 258 × 10^9/L (range 33–1862) for the de-escalation group and 329 × 10^9/L (range 83–789) for the low-dose group. At 3 months, 96% of the de-escalation group achieved <10% BCR-ABL1, compared to 72.1% in the low-dose group. At 6 months, 94.9% of the de-escalation group achieved <1% BCR-ABL1, compared to 83% in the low-dose group. At 12 months, 93.7% of the de-escalation group achieved <0.1% BCR-ABL1, compared to 79.5% in the low-dose group. Adverse events included anemia (4 in de-escalation vs. 3 in low-dose), neutropenia (3 vs. 2), thrombocytopenia (17 vs. 8), gastrointestinal side effects (10 vs. 12), pleural-effusion (2 vs. 1), fever (2 vs. 1), transaminitis (2 in each group), skin rash/pigmentation (14 vs. 4), weight gain (1 vs. 5), periorbital puffiness (3 in de-escalation), hair-fall (1 in de-escalation), and joint and muscle pain (6 in de-escalation). Dose interruptions averaged 52 days (12 patients) in the de-escalation group and 106 days (4 patients) in the low-dose group. At the last follow-up, 2 patients in the de-escalation group switched before de-escalation due to severe toxicity, 2 were censored as defaulters, and 14 were on dasatinib 100mg awaiting de-escalation. Forty-seven patients were de-escalated per protocol; 2 switched to another TKI due to loss of response (median time 5 months, molecular recurrence rate: 4.2%), 3 switched due to toxicity, and 42 continued dasatinib 50mg. In the low-dose cohort, 4 patients lost response (median time 14 months, molecular recurrence rate: 6.3%). No progression to advanced-phase CML or deaths occurred in either cohort.

In conclusion, the dasatinib de-escalation strategy showed high efficacy and safety, with most patients achieving significant molecular responses and manageable adverse events. The de-escalation cohort had better response rates at 3, 6, and 12 months compared to the low-dose dasatinib cohort. These findings support dasatinib de-escalation as a viable treatment approach for chronic myeloid leukemia patients.