Dasatinib and Imatinib-Induced Reductions in BCR-ABL Transcript Levels Below 10% At 3 Months Are Associated with Improved Responses in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Analysis of Molecular Response Kinetics in the DASISION Trial

In the randomized phase 3 DASISION trial in patients (pts) with newly diagnosed CML-CP, dasatinib showed superior efficacy over imatinib (IM), including higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR) at 24 months, and acceptable tolerability (Hochhaus et al. Haematologica 96: 2011 [Suppl 2; abstract 1011]). Previous studies have shown that molecular response after 3 months of imatinib therapy is predictive for treatment failure and transformation (Hanfstein et al, ASH 2010, abstract 360). Here, an analysis of BCR-ABL kinetics in pts from DASISION after a minimum 24 months of follow-up and a 3-month landmark analysis are presented.

Pts with CML-CP diagnosed within 3 months were randomized to receive dasatinib 100 mg once daily (QD; n=259) or IM 400 mg QD (n=260). Levels of BCR-ABL b2a2 and b3a2 transcripts in peripheral blood were assessed using real-time quantitative PCR by a central independent laboratory (MolecularMD, Portland, OR). For the current analysis, pts with atypical BCR-ABL transcripts were excluded (5 in the dasatinib arm, 3 in the imatinib arm). MMR was defined as a BCR-ABL transcript level of ≤0.1% on the international scale (IS) (≥3-log reduction from the standardized baseline). For PCR negative samples an at least 4.5 log test sensitivity was confirmed. The following events were considered in the progression-free survival (PFS) analysis: increasing WBCs, loss of complete hematologic response or major cytogenetic response, transformation to accelerated/blast phase (AP/BP), or death.

In the dasatinib vs imatinib arms, 24-month cumulative response rates were MMR in 65% vs 47%, BCR-ABL ≤0.01% (MR⁴, ≥4-log reduction) in 29% vs 19%, and BCR-ABL ≤0.0032% (MR^4.5, ≥4.5-log reduction) in 17% vs 9%, respectively. The advantage in MMR rates for dasatinib over imatinib was maintained between 12 and 24 months (18–19% difference). Median time to MMR in all pts irrespective of response (calculated by competing risk analysis) was 20 months shorter for dasatinib compared with imatinib (15 vs 35 months). The median BCR-ABL transcript level decreased faster in the dasatinib arm compared with the imatinib arm (Table). By 3 months, 84% vs 64% of evaluable pts in the dasatinib vs imatinib arms, respectively, had achieved a BCR-ABL level ≤10%. Compared with pts who had not achieved this degree of response, a landmark analysis found that pts who had achieved BCR-ABL ≤10% at 3 months had a higher probability of achieving CCyR by 12–18 month and MMR by 18–24 months, a higher probability of 24-month PFS, and a lower probability of transformation to AP/BP, both in the dasatinib and imatinib arms (Table). Probabilities of subsequent CCyR and MMR among pts who had a BCR-ABL level ≤10% at 3 months showed a higher trend in dasatinib-treated pts compared with imatinib-treated pts.

In pts with newly diagnosed CML-CP, first-line dasatinib results in faster and deeper molecular responses compared imatinib. For pts treated with either dasatinib or imatinib, BCR-ABL reduction to ≤10% at 3 months is associated with increased likelihood of achieving CCyR by 12 months and MMR by 24 months, decreased progression to AP/BP, and increased PFS at 24 months.

Hochhaus:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Pfeizer: Consultancy. Chuah:Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Pavlovsky:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Bradley Garelick:Bristol-Myers Squibb: Employment. Lambert:Bristol-Myers Squibb: Employment. Shah:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy; Ariad: Consultancy, Research Funding.