Introduction
Dasatinib is a second-generation BCR-ABL kinase inhibitor. It has been approved as a second-line treatment for patients with chronic myeloid leukemia (CML) if imatinib therapy fails.
Aim
To determine whether patients who received dasatinib had a higher rate of confirmed complete cytogenetic response by 12 months after the initiation of treatment.
Patient Profile
Adults in whom Philadelphia (Ph) chromosome (Ph)-positive, chronic-phase CML had been diagnosed by means of bone marrow cytogenetic studies performed within 3 months before study entry
Methods
- DASISION was an open-label, multinational, randomized phase 3 trial
- Patients continued to receive the study treatment until the disease progressed or unacceptable toxic effects developed
Study Endpoints
- Primary endpoint: A confirmed complete cytogenetic response by 12 months after the initiation of treatment was the primary end point
- Confirmed complete cytogenetic response was defined as a complete cytogenetic response documented on two consecutive assessments at least 28 days apart
- Secondary endpoint: A major molecular response at any time, the time to a confirmed complete cytogenetic response, and the time to a major molecular response
Follow up
All patients had a minimum follow-up of 12 months
Treatment Duration
The median duration of treatment was 14.0 months in the case of dasatinib and 14.3 months in the case of imatinib
Results
|
Characteristic |
Dasatinib (N = 259) |
Imatinib (N = 260) |
|
Age |
|
|
|
Median — yr |
46 |
49 |
|
Range — yr |
18–84 |
18–78 |
|
>65 yr — no. (%) |
20 (8) |
24 (9) |
|
Sex — no. (%) |
|
|
|
Male |
144(56) |
163(63) |
|
Female |
115(44) |
97(37) |
|
ECOG performance status — no. (%)* |
|
|
|
0 |
213(82) |
205(79) |
|
1 |
46(18) |
53(20) |
|
2 |
0 |
2(1) |
|
Hasford risk — no. (%)† |
|
|
|
Low |
86(33) |
87(33) |
|
Intermediate |
124(48) |
123(47) |
|
High |
49(19) |
50(19) |
|
Time from diagnosis to randomization — mo |
|
|
|
Median |
1 |
1 |
|
Range |
0.03–9.7 |
0.1–8.0 |
|
White-cell count — ×10−9/liter |
|
|
|
Median |
25.1 |
23.5 |
|
Range |
2.5–493.0 |
1.4–475.0 |
|
Platelet count — ×10−9/liter |
|
|
|
Median |
448 |
390 |
|
Range |
58–1880 |
29–2930 |
|
Peripheral-blood blasts — % |
|
|
|
Median |
1.0 |
1.0 |
|
Range |
0.0–10.0 |
0.0–11.0 |
|
Peripheral-blood basophils — % |
|
|
|
Median |
4.0 |
4.0 |
|
Range |
0.0–27.8‡ |
0.0–19.5 |
|
Bone marrow blasts — % |
|
|
|
Median |
2.0 |
2.0 |
|
Range |
0.0–14.0 |
0.0–12.0 |
|
BCR-ABL transcript type — no. (%) |
258(100) |
258 (99) |
|
b2a2 and b3a2 |
253 (98) |
255(98) |
|
b2a3 |
1 (<1) |
1(<1) |
|
b3a3 |
1(<1) |
1(<1) |
|
Rare variant |
3(1) |
1(<1) |
|
Previous therapy for CML — no. (%) |
|
|
|
Hydroxyurea |
189(73) |
190(73) |
|
Anagrelide |
8(3) |
3(1) |
|
Imatinib |
3(1) |
4(2) |
- Eastern Cooperative Oncology Group (ECOG) performance status is graded on a scale of 0 to 5, with 0 indicating that the patient is fully active and able to carry on all predisease activities without restriction and 5 indicating that the patient has died.
- The Hasford risk score is calculated with the use of the following equation: (0.6666 × age score + 0.0420 × spleen size + 0.0584 × blasts + 0.0413 × eosinophils + 0.2039 × baso-phil score + 1.0956 × platelet score ) × 1000. A score of less than 780 is considered to indicate low risk, a score of 780 to 1480, intermediate risk, and a score higher than 1480, high risk.
- Two patients with basophil counts of 26% and 28% at baseline had basophil counts of 19% and 16%, respectively, at screening and were eligible.
- Significantly higher rate of a confirmed complete cytogenetic response by 12 months among patients receiving dasatinib than among patients receiving imatinib (77% vs. 66%, P=0.007)
CCyR: complete cytogenetic response
MMR: Major molecular response
- Responses were achieved more quickly with dasatinib than with imatinib.
- The rates of complete cytogenetic response by 3, 6, and 9 months after the initiation of dasatinib treatment were 54%, 73%, and 78%, respectively
- The rates after the initiation of imatinib treatment were 31%, 59%, and 67%, respectively
- The rates of a major molecular response by 3, 6, and 9 months after the initiation of dasatinib treatment were 8%, 27%, and 39%, respectively, and the rates after the initiation of imatinib treatment were 0.4%, 8%, and 18%, respectively
- The time to a confirmed complete cytogenetic response (hazard ratio for shorter time to response, 1.5; P<0.0001) and major molecular response (hazard ratio for shorter time to response, 2.0; P<0.0001) was significantly shorter with dasatinib treatment than with imatinib treatment
- Across all Hasford risk categories, rates of response by 12 months were higher among patients receiving dasatinib than among patients receiving imatinib
- At 12 months
- The estimated rates of progression-free survival were similar for patients who were receiving dasatinib and those who were receiving imatinib (96% and 97%, respectively).
- The estimated rates of overall survival were 97% among patients receiving dasatinib and 99% among those receiving imatinib.
Safety
- Grade 3 or 4 nonhematologic adverse events occurred infrequently in both treatment groups
- Similar rates of discontinuation of therapy owing to drug-related adverse reactions, including cytopenia, were reported
|
Adverse Event |
Dasatinib (n = 258) |
Imatinib (n = 258) |
||
|
All Grades |
Grade 3/4 |
All Grades |
Grade 3/4 |
|
|
Neutropenia |
65% |
21% |
58% |
20% |
|
Anemia |
90% |
10% |
84% |
7% |
|
Thrombocytopenia |
70% |
19% |
62% |
10% |
|
Superficial Edema |
9% |
0% |
36% |
<1% |
|
Pleural Effusion |
10% |
0% |
0% |
0% |
|
Muscle Inflammation |
4% |
0% |
17% |
<1% |
|
Vomiting |
5% |
0% |
10% |
0% |
Conclusion
- In this study dasatinib demonstrated significantly higher and faster rates of complete cytogenetic response and major molecular response compared with imatinib (which is the current standard of care)
- Dasatinib was well tolerated
Reference
N Engl J Med 2010;362:2260-70.