Results of a Phase II Trial of Dasatinib As Frontline Therapy for Chronic Myeloid Leukemia (CML) In Chronic Phase (CP)

Dasatinib is approximately 300 times more potent than imatinib (IM) in vitro and has significant activity in patients (pts) with CML-CP resistant to or intolerant of IM. In 2005 we initiated a phase II trial to study the efficacy and safety of dasatinib in pts with previously untreated CML-CP.

To determine the outcome of pts with CML-CP treated with front-line dasatinib. The primary endpoint was attainment of major molecular response (MMR) at 12 months (mos).

Pts with previously untreated CML-CP within 6 mos from diagnosis were eligible and received dasatinib 100 mg/day, randomized to either 50 mg twice daily (BID) or 100 mg once daily (QD). After 66 pts were accrued, the BID arm was closed and all subsequent pts were treated with 100 mg QD. No prior therapy was allowed except for IM for no more than 1 month, or hydroxyurea.

From November 2005 to June 2011, 99 pts have been enrolled (66 on the QD schedule, 33 BID). For the purposes of this analysis, we considered all pts with clonal evolution at baseline (n=6) as accelerated phase and excluded them from the present analysis, therefore leaving 93 pts (62QD, 31 BID) for review. Median age was 48 years (yrs) (range 18–82); 56% were male. Median baseline counts: WBC 22.95 K/uL, PB blasts 0%, BM blasts 3%, BM basophils 2%, and platelets 315; 21 pts (23%) had brief prior exposure to IM. Sokal score by distribution: Low (81%), Intermediate (14%), High (5%). Median follow-up is 29 mos (3–67). Of the 80 evaluable pts who were not in CHR at the start of therapy, 79 (98%) achieved CHR. Of 87 evaluable pts (ie, followed for at least 3 mos), 83 (95%) achieved complete cytogenetic response (CCyR). MMR has been achieved in 75 pts (86%), including 54 pts (67%) with complete molecular response (CMR; ≤0.0032% IS). At 6 mos, 79 (94%) pts had achieved a CCyR and 56 (68%) an MMR; corresponding figures at 12 mos are 95% and 73%, respectively. Grade 3–4 non-hematologic toxicity included fatigue (9%), pain and dyspnea (6% each), memory impairment (5%), headache and sensory neuropathy (4% each), nausea, cardiac arrhythmia, and neurologic (3% each) and diarrhea, visual, and pleural effusion (2% each). Grade 3–4 hematologic toxicity (transient) included thrombocytopenia 13%, neutropenia 24%, and anemia 9%. Fifty-two (56%) of 93 pts required transient treatment interruptions and 36 (39%) have required dose reductions. The actual median daily dose for all pts was 100 mg (20–140). Thirteen pts lost CCyR: (including 3 because of non-compliance and 2 transient losses, regained spontaneously). The 24-mo probability of event-free survival (EFS) is 93%.There have been no transformations or deaths on study. Twelve (13%) pts have discontinued therapy: 3 pt's choice, 1 lost to follow up, 4 toxicity (2 pleural effusion, 1 congestive heart failure, 1 headaches), and 4 for loss of major cytogenetic response (MCyR). Three pts have had mutation assessment upon discontinuation and no mutations were identified.

Rapid CCyR occurs in nearly all pts with previously untreated CML-CP treated with frontline dasatinib therapy with a favorable toxicity profile. None of the patients have transformed to AP/BP confirming the efficacy of dasatinib as initial therapy for CML-CP.

Kantarjian:Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Jabbour:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Ravandi:BMS: Honoraria, Research Funding. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.