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Frontiers of Medicine

ISSN 2095-0217

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Front. Med.    2019, Vol. 13 Issue (3) : 344-353    https://doi.org/10.1007/s11684-018-0639-7
RESEARCH ARTICLE
Four-year follow-up of patients with imatinib-resistant or intolerant chronic myeloid leukemia receiving dasatinib: efficacy and safety
Xiaojun Huang1, Qian Jiang1, Jianda Hu2, Jianyong Li3, Jie Jin4, Fanyi Meng5, Zhixiang Shen6, Ting Liu7, Depei Wu8, Jianmin Wang9, Jianxiang Wang10()
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
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Abstract

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.
Keywords chronic myeloid leukemia (CML)      dasatinib      tyrosine kinase inhibitor      long-term follow-up     
Corresponding Author(s): Jianxiang Wang   
Just Accepted Date: 07 June 2018   Online First Date: 31 August 2018    Issue Date: 05 June 2019
 Cite this article:   
Xiaojun Huang,Qian Jiang,Jianda Hu, et al. Four-year follow-up of patients with imatinib-resistant or intolerant chronic myeloid leukemia receiving dasatinib: efficacy and safety[J]. Front. Med., 2019, 13(3): 344-353.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-018-0639-7
https://academic.hep.com.cn/fmd/EN/Y2019/V13/I3/344
Characteristic CML-CP
(n = 59)		 CML-AP
(n = 25)
Median age, year±standard deviation 42.8±11.3 39.5±10.5
Male, n (%) 36 (61.0) 15 (60.0)
ECOG performance status, n (%)
0 25 (42.4) 8 (32.0)
1 34 (57.6) 16 (64.0)
2 0 (0) 1 (4.0)
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  Patient demographics and disease characteristics
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  Patient disposition after 4 years of follow-up
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  Summary of treatment response after 18 months and 4 years of follow-up in patients with CML-CP or CML-AP
Fig.1  Kaplan–Meier curve for progression-free survival in dasatinib-treated CML-CP patients. Two patients did not have cytogenetic assessment data and were excluded from the PFS analysis. PFS, progression-free survival.
Fig.2  Univariate logistic regression subgroup analysis of the relationship between baseline factors and complete cytogenetic response after 4 years of follow-up. Odds ratios were calculated using the lower subgroup odds of complete response in the denominator. CI, confidence interval.
Fig.3  Kaplan–Meier progression-free survival curve by early response (MCyR within 90 days of treatment initiation; green line) or no early response (red line). MCyR, major cytogenetic response.
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  Summary of safety data and the most common adverse events after 4 years of follow-up
% (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  Cumulative incidence of pleural effusion at 6 months, 18 months and 48 months follow-up
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