Dasatinib Treatment Induces Fast and Deep Responses In Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients In Chronic Phase: Clinical Results From a Randomized Phase 2 Study (NordCML006)

Dasatinib is a potent BCR-ABL1 and SRC tyrosine kinase inhibitor, which in vitro is more effective against progenitor and putative leukemia stem cells than imatinib. This may translate into deeper molecular responses in vivo.

We randomized (1:1) 46 newly diagnosed CML patients to receive dasatinib 100 mg or imatinib 400 mg once daily. The primary endpoint of our study was treatment response in stem and progenitor cell fractions (Mustjoki et al, Leukemia 2013). We here summarize the clinical results of the study after a 24-month follow-up focusing on toxicity and standard response evaluation by quantitative BCR-ABL1 PCR and cytogenetics (NCT00852566 www.ClinicalTrials.gov).

Both imatinib and dasatinib treated patients fared well with deeper and faster treatment responses than what has been reported in the registration studies. By karyotyping, dasatinib induced a faster response by 3 months (median of 5% of Ph+ cells in imatinib group vs. 0% in dasatinib group, p=0.01, n=21 in each group), but already by 12 months the difference disappeared, as all evaluable patients were in complete cytogenetic remission. The rate of molecular response MR^3.0 was already at the 3 months time-point better in the dasatinib group (36% vs 8%, p=0.02; see Table), but within 18 months imatinib patients caught up the difference. In contrast, the achievement of deeper therapy responses, MR^4.0 and MR^4.5, was clearly different between the groups and increased over 24 months. After 18 months 64% and 71% of imatinib- and dasatinib-treated patients had achieved MR^3.0 (p=0.59), while the MR^4.0 rates were 23% and 62% (p=0.009) and MR^4.5 rates 4% and 41% (0.003) (see Table below). The difference in median transcript levels was approximately 1 log (>10-fold difference) in all time-points after 3 months of therapy (see Table below).

A total of 7 patients (30%) in both groups discontinued assigned treatment. Main drug-related toxicities were as expected. Dasatinib-induced serosal inflammation (pleural/pericardial effusions) was more frequent than in registration studies (6 patients, 27%). In 4 patients (18%) this led to therapy discontinuation, despite of drug interruption and dose reductions. In the imatinib group 3 patients discontinued due to drug-related toxicity (liver toxicity, rash and severe hypogammaglobulinemia with recurrent infections). Disease progression occurred in one dasatinib-treated patient (cytogenetic progression with the appearance of V299L mutation at month 9) and two imatinib-treated patients (blastic transformation at month 2 and molecular progression at month 18). The patient in blast phase has been transplanted and is currently in molecular remission. No CML-related deaths occurred, but one patient died from lung cancer.

Dasatinib induced faster and deeper molecular responses than imatinib and overall responses were better in both groups than in the registration studies. Relatively high rate of serosal toxicity was observed among the dasatinib-treated patients, but this had no adverse effect on response. Upcoming studies will show if the deeper treatment responses induced by dasatinib therapy translate into increased probability of successful therapy discontinuation.

Hjorth-Hansen:Pfizer: Honoraria, Travel, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Novartis: Honoraria, Travel Other; Merck: Research Funding. Richter:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; Bristol-Myers Squibb: Consultancy, Honoraria, Travel, Travel Other. Porkka:BMS: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Mustjoki:Novartis: Honoraria; BMS: Honoraria, Research Funding.