ORLANDO, Fla.—Both dasatinib (DAS) and imatinib (IM) are highly effective and generally well tolerated in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP), results of an open-label phase 2 study have found.
The optimal tyrosine kinase inhibitor (TKI) for this patient population remains unknown. DAS—a more potent TKI in vitro than IM—did induce deeper molecular responses at 12 months; however, it was associated with more grade 3-4 toxicity than IM, and whether this response will translate into improved long-term outcomes requires additional follow-up, said Jerald P. Radich, MD, of Fred Hutchinson Cancer Research Center, Seattle, Wash.
In this study, four North American cooperative groups—SWOG, ECOG, CALGB, and NCIC-CTG—randomized patients with newly diagnosed CML-CP to oral IM 400 mg once daily or oral DAS 100 mg once daily. Primary end point was >4 log reduction in BCR‑ABL transcript at 12 months. At 240 evaluable patients, the study design provided >90% power to detect a difference in this end point of >20 percentage points (two-sided alpha=5%), Dr. Radich and colleagues reported during the 52nd American Society of Hematology Annual Meeting and Exposition.
From December 2006 to February 2009, 253 patients were randomized; 7 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 for the 246 patients are shown in Table 1.Please click here for more study data. Median age was 49 years (range, 18-90 years); 60% were male. Hasford intermediate risk was 35% and high risk, 30%. Eighteen patients (15%) in the DAS group and 13 (11%) in the IM group discontinued study drug due to a variety of toxicities. Eleven patients, 3 (2%) in the DAS group and 8 (7%) in the IM group, discontinued by refusing to continue treatment; 36 others, 12 (10%) in the DAS arm and 24 (20%) in the IM arm, discontinued for other reasons, most often physician or patient concerns about inadequate response or disease 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; Wilcoxon P=0.048), although the proportions achieving >4 log or >4.5 log reductions did not differ significantly (molecular response at 12 months was based on 189 rather than the planned 240 patients, but this provided >80% power to detect a difference of >20 percentage points).
Rates of hematologic CR (HemCR) and cytogenetic CR (CCyR) were not significantly higher with DAS, although 11% of DAS and 5% of IM patients were not adequately assessed for HemCR; CCyR data were available for only 51% of patients. Overall survival (OS) and progression-free survival (PFS) were similar in the two arms, with very few deaths, relapses, or progressions. Among patients with HemCR, 2-year relapse-free survival was 97% in the DAS arm and 95% in the IM arm.
No patient died due to toxicities. The most common grade 3/4 adverse events (AEs) were hematologic, including thrombocytopenia (<50×109/L) in 18% of those receiving DAS and 8% of those receiving IM (P=0.024). Several grade 4 nonhematologic toxicities were reported for 6% of patients receiving DAS but none receiving IM. An additional 30% of patients in the DAS arm and 17% in the IM arm experienced several grade 3 nonhematologic AEs, while another 57% and 79%, respectively, had nonhematologic grade 1 to 2 AEs. Pleural effusion of any grade was reported for 11% of DAS-treated and 2% of IM-treated patients (P=0.0017); <2% in either arm were grade 3.
Seven patients have died, all >8 months after entering the study. Three died in the DAS arm: 1 at 8 months after progression to blast crisis, one from lung cancer diagnosed 10 months after initiation of treatment, and 1 in an automobile accident. Two patients receiving IM died of CML. Two others (ages 70 and 75 years at treatment start) died of cardiac arrest unrelated to CML or treatment.
This study presents further evidence that DAS is more efficacious than 400 mg IM in newly diagnosed chronic phase CML patients with significantly deeper molecular responses at 12 months and a trend toward higher CCyR, but not significantly higher rates of >4 log or >4.5 log reduction in BCR-ABL transcript levels. Each drug has different toxicities, with DAS associated with more grade 3-4 toxicities.
At the conclusion of the presentation Dr. Radich also showed comparison data of Study S0325 to the DAISISON Study, where similar results were seen across all arms with respect to CCyR, MMR, and PFS. Please click here for more study data.