Impact of Dose Reductions and Interruptions Due to Adverse Events (AEs) on Efficacy in Newly Diagnosed Chronic Myeloid Leukemia in ChronicPhase (CML-CP) Patients (pts) Receiving Either Dasatinib (D) or Imatinib(IM): Analysis of the DASISION Trial

24-month follow-up of pts with newly diagnosed CML-CP in the DASISION trial demonstrated both a high rate of complete cytogenetic response (CCyR) with dasatinib (D) and higher and faster rates of major molecular response (MMR) with D over imatinib (IM), supporting the use of D 100 mg once daily as a first-line treatment option for newly diagnosed CML-CP. Discontinuations due to adverse events (AEs) occurred in 7% with D and 5% with IM. Median dose intensity for D and IM were 99.5 mg/day and 400 mg/day, respectively (Kantarjian JCO 2011:29;Abs 6510). A retrospective analysis of pts from DASISION was performed to evaluate the impact of dose reductions and interruptions due to AEs on efficacy of D or IM in newly diagnosed CML-CP.

Pts with newly diagnosed CML-CP received D 100 mg QD (N=258) or IM 400 mg QD (N=258). The primary endpoint was confirmed CCyR by 12 months. In DASISION, up to two dose reductions were permitted for AEs; dose reduction levels were 80 mg/50 mg for D and 300 mg/200 mg for IM. Dose interruptions were permitted for management of AEs. Upon resolution or improvement of AEs to ≤ Grade 1, pts could resume therapy at an appropriate dose based on initial severity of the AE. Efficacy was evaluated for pts with or without dose reductions and/or interruptions due to AEs at any time. Efficacy was also evaluated for pts with first dose interruption and/or reduction due to AEs within ≤6 or >6 months of their first dose who remained on treatment for at least 6 months, in order to reduce selection bias of pts with longer duration of therapy. Pts with dose reduction and/or interruption for reasons other than AEs (dosing error, medical procedure) were excluded from all analyses.

134 D pts (52%) and 92 IM pts (36%) had dose reduction and/or interruption for AE management at the DASISION 24-month update. First dose reduction and/or interruption due to non-hematologic AEs occurred in 59 (23%) D and 40 (16%) IM pts and hematologic AEs in 75 (29%) D and 52 (20%) IM pts. Pts with dose reduction and/or interruption for reasons other than AE management were excluded, including 21 (8%) D pts and 19 (7%) IM pts. The median duration of first dose interruption due to AEs was approximately 2 weeks on both arms. CCyR and MMR rates with D were comparable whether pts did or did not have their dose reduced and/or interrupted at any time (Table). D pts who had dose reduction and/or interruption had generally higher rates of responses than IM pts overall and in those without an IM dose reduction and/or interruption. The timing of dose reduction and/or interruption appeared to have a potential impact as response rates were higher when dose reduction and/or interruption occurred >6 months after the first dose of either drug (Table). CCyR and MMR rates with D remained higher than with IM when dose reduction and/or interruption occurred ≤6 months from first dose. Similarly, both CCyR and MMR were higher for D than with IM if dose reduction and/or interruption occurred >6 months from the first dose.

Results of this analysis suggest that CML-CP pts receiving dasatinib achieved similar response rates despite dose modification for the management of AEs. Data for pts with and without dose reduction and/or interruption due to AEs are consistent with DASISION 24-months results, showing higher rates of response with dasatinib than with imatinib.

Kantarjian:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Quintas-Cardama:Bristol-Myers Squibb: Honoraria. Guilhot:Novartis: Honoraria; Bristol-Myers Squib: Honoraria; Pfizer: Honoraria; Celgene: Honoraria. Zhu:Bristol-Myers Squibb: Employment. Hong:Bristol-Myers Squibb: Employment, Equity Ownership. Cain:Bristol-Myers Squibb: Employment, Equity Ownership. Cortes:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.