Phase 2 Study of Dasatinib in Chinese Patients (Pts) with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) or Advanced Phase Who Are Resistant to or Intolerant of Imatinib (IM)
Authors: Wang Jianxiang , Huang Xiaojun , Hu Jianda , Li Jianyong , Jin Jie , Meng Fanyi , Shen Zhixiang , Liu Ting , Wu Depei , Wang Jianmin 
Published: October 2019

Abstract
Abstract 4434

Background:
CML has a lower incidence in China than in Western countries and appears to affect a younger population (Au, Int J Hematol 2009). In recent years, IM has become the first-line standard of care across Asia for pts with newly diagnosed CML. In a cohort of Chinese pts, >25% of evaluable pts in CP failed to achieve a CCyR with first-line IM, and response rates were significantly lower in pts with accelerated-phase (AP) or blast-phase (BP) CML (Wang, J Exp Clin Cancer Res 2010). Dasatinib is a highly potent second-generation BCR-ABL inhibitor that has established efficacy and safety in pts with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) after prior imatinib therapy. Dasatinib is approved by various regulatory authorities worldwide for first-line treatment of Philadelphia chromosome-positive (Ph+) CML in CP. Limited efficacy and safety data are available for second-generation BCR-ABL inhibitors in Chinese pts with CML or Ph+ ALL after imatinib therapy.

Methods:
In an open-label, single-arm phase 2 study, Chinese pts aged ≥18 years with IM resistant/intolerant CML or Ph+ ALL received dasatinib 100 mg once daily (CP) or 70 mg twice daily for AP/BP or Ph+ ALL. Bone marrow cytogenetic evaluation was performed at months 3 and 6, then every 6 months in CP pts, and was optional for pts with AP/BP or Ph+ ALL. Primary study objectives were to assess rates of major cytogenetic response (MCyR) in CP pts and complete and overall hematologic response (CHR and OHR) in pts with AP/BP or Ph+ ALL. OHR was defined as CHR, no evidence of leukemia, or return to CP. Treatment continued until disease progression or intolerable toxicity.

Results:
Of 140 enrolled pts, 121 pts had received ≥1 dose of dasatinib and were evaluable (59 with CP, 25 with AP, 35 with BP, and 2 with Ph+ ALL). Of pts with CML-CP or AP/BP/Ph+ ALL, 52 (88%) and 53 (85%) were IM resistant, 4 (7%) and 5 (8%) were IM intolerant, and 3 (5%) and 4 (6%) were both IM resistant and intolerant. Median time from original CML diagnosis to first dasatinib dose was 46.3 months (CP) and 50.2 months (AP/BP/Ph+ ALL). More than half of pts had received prior interferon therapy. At last follow-up, dasatinib therapy had been discontinued by 7 pts (12%) with CP and 43 pts (69%) with AP/BP/Ph+ ALL, due to disease progression or loss of response in 2% and 35%, study drug toxicity in 2% and 11%, stem-cell transplant in 0% and 5%, death in 2% and 2%, and other reasons in 7% and 16%, respectively. After a minimum of 12 months follow-up, MCyR was achieved by 30 pts with CP (51%), 10 pts with AP (40%), and 8 pts with BP/Ph+ ALL (22%). In pts with CP, median time to MCyR was 12 weeks and no patient lost MCyR. Complete cytogenetic response was achieved by 25 pts with CP (44%), 7 pts with AP (28%), and 6 pts with BP/Ph+ ALL (16%). CHR was achieved by 54 pts with CP (92%), 13 pts with AP (52%), and 6 pts (16%) with BP/Ph+ ALL. In CP pts, most (51/54) who achieved CHR did so within 2 months. Median times to CHR were 16 and 12 weeks for pts with AP and BP/Ph+ ALL, respectively. After 12 months, 3 pts in CP, 2 pts in AP, and 1 pt in BP had lost their CHR. OHR was achieved by 23 and 13 pts (92% and 35%) with AP and BP/Ph+ ALL, respectively. In safety assessments (Table), grade 3/4 cytopenia was frequent but managed by dose interruption/reduction or supportive care, with 1 pt discontinued for cytopenia. Pleural effusion of any grade occurred in 15%, 20%, and 22% of pts with CP, AP, and BP/Ph+ ALL, respectively. Grade 3/4 pleural effusion occurred in 1 pt with CML-CP (2%) and 5 pts with AP/BP/Ph+ ALL (8%).

Conclusions:
The current study confirms the efficacy and safety of dasatinib in Chinese pts with CML or Ph+ ALL that is resistant or intolerant to IM. Results were consistent with data from global trial populations.

Disclosures:
No relevant conflicts of interest to declare.