In all, 150 imatinib-resistant CML-CP patients were randomized 2:1 to 140 mg daily dasatinib (n=101) or 800 mg daily imatinib (n=49). Crossover to the alternate treatment was permitted after confirmed progression. With a median follow-up of 15 months, CHRs were observed in 93% and 82% of patients receiving dasatinib and HD imatinib (P=0.034), respectively.
Dasatinib resulted in a higher rate of MCyR (52%) than HD imatinib (33%) (P=0.023). This included CCyR in 40% and 16% of patients (P=0.004), respectively. MMR rates were also more frequent with dasatinib (16% vs 4%; P=0.038).
Treatment failure (hazard ratio [HR], 0.16; P,0.001) and PFS (HR, 0.14; P,0.001) both favored dasatinib.25 A 2-year follow-up report of this study showed that dasatinib demonstrated higher rates of CHR (93% vs 82%; P=0.034), MCyR (53% vs 33%; P=0.017), and CCyR (44% vs 18%; P=0.0025). At 18 months, the MCyR was maintained in 90% of patients on the dasatinib arm and in 74% of patients on the HD imatinib arm. MMR rates were also more frequent with dasatinib than with HD imatinib (29% vs 12%; P=0.028).
The estimated PFS also favored dasatinib (P=0.0012).26 Dasatinib was the first TKI approved to treat patients with imatinib-resistant CML-CP. There were no other randomized clinical trials comparing efficacy of the 2G-TKIs with escalated dose imatinib in standard dose imatinib-resistant patients.
However, the rates of cytogenetic and molecular responses achieved in patients treated with 2G-TKIs frontline are considerably higher relatively to those achieved by patients treated with HD imatinib (Table II).
|Table II – Selected trials comparing standard- or high-dose imatinib or second-generation TKIs in newly diagnosed patients with CML|
|Study||Follow-up (months)||Random||CCyR (%)||MMR (%)|
|TOPS||12||IM 400 mg
IM 800 mg
|German Study IV||12||IM 400 mg
IM 800 mg
|ENESTnd||24||NILO 300 mg BID
NILO 400 mg BID
IM 400 mg
|DASISION||18||DASA 100 mg
IM 400 mg
|Abbreviations: BID, twice daily; CML, chronic myeloid leukemia; CCyR, complete cytogenetic response; DASA, dasatinib; IM, imatinib; MMR, major molecular response; NILO, nilotinib; TKI, tyrosine kinase inhibitor.|
The recent ELN guidelines for management of CML-CP do not recommend imatinib dose escalation in case of treatment failure on the standard imatinib dose4 since the 2G-TKIs (nilotinib, dasatinib, and bosutinib) and the 3G-TKI (ponatinib) appeared to be more effective in such circumstances.27–29