Phase II Clinical Trial Results of Dasatinib for Frontline Therapy in Patients with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP)

Background: 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.

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

Methods: 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 <1 month, or hydroxyurea.

Results: From November 2005 to August 2014, a total of 155 pts have been enrolled. For this analysis, we included only those pts with a minimum of 12 mos follow-up: 107 pts (77 QD, 30 BID). Median age was 48 years (yrs) (range 16–83 yrs). Median baseline counts: WBC 26.4 K/uL, peripheral blood blasts 0%, bone marrow blasts 2%, and platelets 333 K/uL. Twenty-seven pts (25%) had brief prior exposure to IM. Sokal score by distribution: Low (76%), Intermediate (21%), High (4%). Median follow-up is 62.9 mos (11.7 - 104.1 mos). Of the 99 evaluable pts who were not in CHR at the start of therapy, 99 (100%) achieved CHR. Of 105 evaluable pts (ie, followed for at least 3 mos), 105 (100%) achieved complete cytogenetic response (CCyR). MMR has been achieved in 94 pts (90%), including 59 pts (56%) with complete molecular response (CMR; minimum 100,000 ABL copies). BCR-ABL/ABL <10% at 3 mos occurred in 100/106 evaluable (94%) and at 6 mos in 98/104 evaluable (94%). At 6 mos, 93/102 evaluable (91%) pts had achieved a CCyR and 69/101 evaluable (68%) an MMR; corresponding figures at 12 mos are 92/97 pts evaluable (95%) and 73/95 pts evaluable (77%), respectively. Fifty-eight pts (54%) have required at least one dose reduction (most common reasons: 22 pts had dose reductions due to pleural effusions, 8 due to neurologic/headaches, 4 due to thrombocytopenia). The actual median daily dose for all pts was 80mg (20–140mg). Five pts lost CCyR: (2/5 of these pts who lost CCyR ultimately progressed to accelerated phase (CML-AP)). The 3-yr and 5-yr overall survival (OS), event-free survival (EFS), transformation-free survival (TFS), and failure-free survival (FFS) are shown in the Table. There have been two deaths on study (1 pt: 74 yr-old woman with sepsis/infection; 1 pt: 53 yr-old man with morbid obesity and hypertension who died of unknown causes). Twenty-six (24%) pts have discontinued therapy: 11 due to toxicity (most commonly due to pleural effusion in 7 pts), 5 pt choice, 5 lost CCyR, 2 died on study, 2 pt non-adherence, 1 due to development of T315I mutation.

Conclusion: Rapid CCyR occurs in nearly all pts, and MMR was achieved in 90% of pts with previously untreated CML-CP treated with frontline dasatinib therapy with a favorable toxicity profile. Deep responses occur early. Only two patients experienced transformation to CML-AP, and only one patient developed T315I mutation. These results confirm the sustained efficacy of dasatinib as initial therapy for CML-CP.

*Definitions:EFS: includes, at any time on study: International Randomized Study of Interferon and STI571 trial (IRIS)-defined events, which includes loss of major cytogenetic response, loss of complete hematologic response, transformation to accelerated or blast phase, death from any cause while on study. FFS: includes loss of complete cytogenetic response, failure to achieve response at set times as defined by European Leukemia Net, treatment intolerance, or treatment discontinuation for any reason while on study. TFS: measured from start of therapy to date of transformation to accelerated or blast phases while on therapy or to date of last follow-up.