DASISION Study: Efficacy and Safety of Dasatinib versus Imatinib for the First-Line Treatment of Chronic-phase CML

Table of Content

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

Table 1: Baseline Characteristics

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)
Figure 1: Response rates among patients receiving dasatinib vs imatinib

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
Table 2:  Drug-Related adverse events that occurred in at least 10% of treated patient

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.