A Randomized Phase II Trial of Dasatinib 100 Mg Vs Imatinib 400 Mg In Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP): The S0325 Intergroup Trial

The optimal tyrosine kinase inhibitor (TKI) for patients (pts) with newly diagnosed CML-CP is unknown. While dasatinib (DAS) is a more potent TKI in vitro than imatinib (IM), it is unclear if this will translate into improved long-term clinical outcomes for pts with newly diagnosed CML-CP. In this open-label phase II trial pts with newly diagnosed CML-CP were randomized to IM 400 mg po qd or DAS 100 mg po qd by four North American cooperative groups (SWOG, ECOG, CALGB, NCIC-CTG). The primary endpoint was >4 log reduction in BCR-ABL transcript at 12 months (mos). The study design, with 240 evaluable pts, provided >90% power to detect a difference in this endpoint of >20 percentage points (two-sided alpha=5%).

253 pts were randomized (12/2006 to 2/2009). Seven were ineligible, primarily due to diagnosis other than CML-CP, or nonevaluable because they received no protocol treatment or withdrew consent. Pretreatment characteristics were balanced between the arms.

Outcomes of the 246 included pts (age 18–90, median 49; 60% male; 35% / 30% with Hasford intermediate / high risk) are shown in Table 1. Eighteen DAS (15%) and 13 IM 400mg (11%) pts discontinued study drug because of a variety of toxicities. Eleven pts (3 DAS [2%], 8 IM 400mg [7%]) discontinued due to refusal, and 36 others (12 DAS [10%], 24 IM 400mg [20%]) for other reasons, most often physician or pt concerns about inadequate response, recurrence or progression. Molecular response at 12 months was deeper in the DAS arm (median 3.3 log reduction in BCR-ABL transcript level vs 2.8 with IM 400mg; Wilcoxon P=0.048), although the proportions achieving >4 log or >4.5 log reductions did not differ significantly (molecular response at 12 mos was based on 189 rather than the planned 240 pts, but this provided >80% power to detect a difference of >20 percentage points). The rates of hematologic CR (HemCR) and cytogenetic CR (CCyR) were not significantly higher with DAS, though 11% and 5% of DAS and IM 400mg pts were not adequately assessed for HemCR, and CCyR data were only available for 51% of pts. Overall survival (OS) and progression-free survival (PFS) were similar in the two arms, with very few deaths, relapses or progressions. Among pts with HemCR, 2-year relapse-free survival was 97% in the DAS arm, 95% in the IM 400mg arm.

There were no fatal toxicities. The most common grade 3 and 4 toxicities were hematologic, including thrombocytopenia (<50×10⁹/L) in 18% and 8% of DAS and IM 400mg pts, respectively (P=0.024). A variety of grade 4 non-hematologic toxicities were reported for 6% of DAS pts but no IM 400mg pts. An additional 30% and 17% of DAS and IM 400mg pts had a variety of grade 3 non-hematologic toxicities, while another 57% and 79% had non-hematologic grade 1–2 toxicities. Pleural effusion of any grade was reported for 11% and 2% of DAS and IM 400mg pts (P=0.0017); <2% in either arm were grade 3.

Seven pts have died, all >8 months after entering the study. Three DAS pts died: one at 8 months after progression to blast crisis, one from lung cancer diagnosed 10 months after DAS started, and one in an automobile accident. Two IM 400mg pts died of CML, and two others (ages 70 and 75 at treatment start) of cardiac arrest unrelated to CML or treatment.

Both IM 400mg and DAS are highly effective and generally well-tolerated therapies for newly diagnosed CML-CP. DAS induced deeper molecular responses at 12 months, but not significantly higher rates of >4 log or >4.5 log reduction in BCR-ABL, compared to IM 400mg. 12-month PFS and OS were similar between the two arms, with very few events so far. DAS was associated with more grade 3–4 toxicity. Clinical follow-up is continuing to study whether the short-term deeper molecular response seen with DAS will translate into improved long-term outcomes.

Radich:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy. Kopecky:Bristol-Myers Squibb: Research Funding. Kamel-Reid:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Larson:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Emanuel:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Genzyme: Consultancy. Lipton:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Deininger:Bristol-Myers Squibb: Advisory Board, Consultancy, Research Funding; Novartis: Advisory Board, Consultancy. Druker:MolecularMD: Equity Ownership; Novartis: Clinical Trial Funding; Bristol-Myers Squibb: Clinical Trial Funding.