1. Peking University People’s Hospital, Beijing 100044, China 2. Fujian Medical University Union Hospital, Fuzhou 350004, China 3. The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China 4. The First Affiliated Hospital of The College of Medicine, Zhejiang University, Hangzhou 310058, China 5. Guangzhou Nanfang Hospital, Guangzhou 510515, China 6. Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China 7. West China Hospital, Sichuan University, Chengdu 610041, China 8. The First Affiliated Hospital of Soochow University, Suzhou 215006, China 9. Changhai Hospital of Shanghai, Shanghai 200433, China 10. The Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300020, China
Dasatinib is a highly effective second-generation tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML). In 2007, a pivotal phase-2 study of dasatinib as second-line treatment was initiated in 140 Chinese CML patients. This report from the 4-year follow-up revealed that 73% of 59 patients in chronic phase (CML-CP) and 32% of 25 patients in accelerated phase (CML-AP) remained under treatment. The initial dosage of dasatinib for CML-CP and CML-AP patients were 100 mg once daily and 70 mg twice daily (total= 140 mg/day), respectively. The cumulative major cytogenetic response (MCyR) rate among patients with CML-CP was 66.1% (versus 50.8% at 18 months), and the median time to MCyR was 12.7 weeks. All CML-CP patients who achieved MCyR after a 4-year follow-up also achieved a complete cytogenetic response. The cumulative complete hematological response (CHR) rate among patients with CML-AP was 64% (16/25), with three CML-AP patients achieving CHR between 18 months and 4 years of follow-up; the median time to CHR was 16.4 weeks. The adverse event (AE) profile of dasatinib at 4 years was similar to that at 6 and 18 months. The most frequently reported AEs (any grade) included pleural effusion, headache, and myelosuppression. These long-term follow-up data continue to support dasatinib as a second-line treatment for Chinese patients with CML.
Median time between diagnosis and first dose of dasatinib, month (range)
46.3 (5.4–214.6)
72.0 (18.0–140.7)
Years of prior imatinib therapy, n (%)
<1
13 (22.0)
4 (16.0)
1–3
34 (57.6)
13 (52.0)
>3
12 (20.3)
8 (32.0)
Highest dose (mg/d) of prior imatinib, n (%)
400–600
46 (78.0)
15 (60.0)
>600
13 (22.0)
10 (40.0)
Best cytogenetic response to imatinib, n (%)
Complete
4 (6.8)
1 (4.0)
Minimal
9 (15.3)
2 (8.0)
Minor
11 (18.6)
6 (24.0)
Partial
16 (27.1)
11 (44.0)
None
17 (28.8)
1 (4.0)
Unable to determine
2 (3.4)
4 (16.0)
Patients resistant to prior imatinib, n (%)
55 (93.2)
23 (92.0)
Patients intolerant to prior imatinib, n (%)
7 (11.9)
4 (16.0)
Prior therapy other than imatiniba, n (%)
Anyb
51 (86.4)
25 (100.0)
Interferon
31 (52.5)
19 (76.0)
Hydroxyurea or anagrelide
48 (81.4)
22 (88.0)
Cytarabine
9 (15.3)
10 (40.0)
Tab.1
CML-CP (n = 59)
CML-AP (n = 25)
On study treatment, n (%)
43 (72.9)
8 (32.0)
Discontinued treatment, n (%)
16 (27.1)
17 (68.0)
Reason for treatment discontinuation, n (%)
Adverse event unrelated to study drug
1 (1.7)
1 (4.0)
Death
1 (1.7)
0 (0)
Disease progression
5 (8.5)
7 (28.0)
Lost to follow-up
1 (1.7)
0 (0)
Study drug toxicity
1 (1.7)
2 (8.0)
Withdrawn consent
3 (5.1)
2 (8.0)
Stem cell transplant
0 (0)
0 (0)
Patient request
0 (0)
1 (4.0)
Unknown
4 (6.8)
4 (16)
Median duration of dasatinib treatment, months (range)
50.1 (1.6–60.7)
34.1 (3.4–61.6)
Tab.2
Follow-up period
18-month
4-year
CML-CP (n = 59)
Cumulative MCyR, n (%) [95% CI]
30 (50.8) [37.5–64.1]
39 (66.1) [52.6–77.9]
Median time to MCyR, week (range)
12.7 (4.3–48.0)
12.7 (4.3–206.1)
Cytogenetic responsea, n (%)
CCyR
26 (44.1)
39 (66.1)
PCyR
4 (6.8)
0 (0)
Minor
10 (16.9)
5 (8.5)
Minimal
8 (13.6)
7 (11.9)
No response
9 (15.3)
6 (10.2)
Unable to determineb
2 (3.4)
2 (3.4)
CML-AP (n = 25)
CHR, n (%) [95% CI]
13 (52.0) [31.3–72.2]
16 (64.0)[42.5–82.0]
Median time to CHR, weeks (range)
16.0 (11.7–52.1)
16.4 (11.7–88.6)
Best hematologic response, n (%)
No Response
2 (8.0)
2 (8.0)
Minor
2 (8.0)
2 (8.0)
No evidence of leukemia
8 (32.0)
5 (20.0)
Complete
13 (52.0)
16 (64.0)
Cumulative MCyR, n (%) [95% CI]
10 (40.0) [21.1–61.3]
10 (40.0) [21.1–61.3]
Median time to MCyR, weeks (range)
12.1[11.7-48.9]
Not available
Cytogenetic responsea, n (%)
CCyR
9 (36.0)
9 (36.0)
PCyR
1 (4.0)
1 (4.0)
Minor
2 (8.0)
2 (8.0)
Minimal
4 (16.0)
5 (20.0)
No response
7 (28.0)
6 (24.0)
Unable to determinec
2 (8.0)
2 (8.0)
Tab.3
Fig.1
Fig.2
Fig.3
AEs, n (%)
CML-CP (n = 59)
CML-AP (n = 25)
Any grade
Grade 3–4
Any grade
Grade 3–4
≥1 drug-related AE
41 (69.5)
11 (18.6)
21 (84.0)
16 (64.0)
Treatment discontinuation due to AEs
7 (11.9)
3 (5.1)
2 (8.0)
1 (4.0)
Most common drug-related AEs
(≥10% of patients)
Pleural effusion
14 (23.7)
2 (3.4)
10 (40.0)
0
Headache
13 (22.0)
0 (0)
3 (12.0)
0
Thrombocytopenia
7 (11.9)
7 (11.9)
6 (24.0)
6 (24.0)
Diarrhea
4 (6.8)
1 (1.7)
5 (20.0)
2 (8.0)
Neutropenia
4 (6.8)
4 (6.8)
6 (24.0)
6 (24.0)
Pulmonary hypertension
4 (6.8)
1 (1.7)
2 (8.0)
0
Pneumonia
0
0
5 (20.0)
1 (4.0)
Lung infection
0
0
4 (16.0)
2 (4.0)
Pericardial effusion
2 (3.4)
0
3 (12.0)
1 (4.0)
Tab.4
% (n/n)
6 months follow-up
18 months follow-up
48 months follow-up
CML-CP
13.6 (8/59)
15.3 (9/59)
23.7 (14/59)
CML-AP
20.0 (5/25)
20.0 (5/25)
40.0 (10/25)
Tab.5
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