Table 1 Efficacy of 2G TKIs in newly diagnosed CML-CP

Dasatinib. DASISION (NCT00481247) [17]: phase 3 multicenter trial comparing dasatinib with imatinib in the first-line treatment of ND Ph + CML-CP

Aged ≥ 18 years

Newly diagnosed Ph + CML-CP

ECOG PS 0–2

No prior TKI treatment*

No baseline pleural effusion

Select CV conditions not excluded: myocardial infarction > 6 months, congestive heart failure > 3 months, or uncontrolled angina > 3 months prior to enrollment

Confirmed CCyR by 12 months (primary endpoint):

 Dasatinib 77%; imatinib 66% (P = 0.007)

MMR at 12 months:

 Dasatinib 46%; imatinib 28% (P = 0.0001)

Cumulative 5-year MMR rate:

 Dasatinib 76%; imatinib 64% (P = 0.002)

Cumulative 5-year MR^4.5 rate:

 Dasatinib 42%; imatinib 33% (P = 0.0251)

Drug-related pleural effusion:

 Dasatinib 28%; imatinib 1%

Discontinuations:

 Dasatinib (n = 100, 39%)

 Imatinib (n = 96, 37%)

Dasatinib:

 Intolerance (n = 42, 16%)

 Progression or treatment failure (n = 28, 11%)

Imatinib:

 Progression or treatment failure (n = 36, 14%)

 Intolerance (n = 17, 7%)

Nilotinib. ENESTnd (NCT00471497) [18]: phase 3, randomized, open-label, multicenter trial of nilotinib (300 mg or 400 mg BID) versus imatinib in patients with ND Ph + CML-CP

Aged ≥ 18 years

Ph + CML-CP diagnosed within 6 months of diagnosis

ECOG PS 0–2

No cardiovascular conditions

No T315I mutations

MMR at 12 months (primary endpoint):

 Nilotinib 300 mg 44%; nilotinib 400 mg 43%; imatinib 22% (P < 0.001 nilotinib vs. imatinib)

5-year MR^4.5:

 Nilotinib 300 mg 54% (n = 151/279); nilotinib 400 mg, 52% (n = 147/277); imatinib 31% (n = 89/280) (P < 0.0001 nilotinib vs. imatinib)

Estimated progression-free survival:

 Nilotinib 300 mg 96%; imatinib 91% (P = 0.0204)

Estimated overall survival:

 Nilotinib 300 mg, 96%; imatinib, 92% (P = 0.0266)

Grade 3/4 cardiovascular events:

 Nilotinib 300 mg 5% (n = 13/279); nilotinib 400 mg 9% (n = 24/277); imatinib 2% (n = 5/280)

Grade 3/4 elevated glucose levels:

 Nilotinib 300 mg 7% (n = 20/279); nilotinib 400 mg 7% (n = 19/277); imatinib < 1% (n = 1/280)

Imatinib discontinuations (n = 139):

 Suboptimal response/treatment failure (n = 59)

 AEs/abnormal laboratory values (n = 38)

Nilotinib 300 mg discontinuations (n = 110):

 AEs/abnormal laboratory values (n = 34)

 Suboptimal response/treatment failure (n = 34)

Nilotinib 400 mg discontinuations (n = 105):

 AEs/abnormal laboratory values (n = 56)

 Withdrawal of consent (n = 16)

 Suboptimal response/treatment failure (n = 13)

Bosutinib. BFORE (NCT02130557) [15, 25, 102, 103]: phase 3, randomized, open-label, multicenter trial of bosutinib versus imatinib in patients with ND Ph + or Ph-/BCR::ABL1 + CML-CP

Aged ≥ 18 years

Newly diagnosed Ph + or Ph-/BCR::ABL1 + CML-CP (≤ 6 months from initial diagnosis)

ECOG PS 0–1

No prior treatment, including TKIs

MMR at 12 months (primary endpoint):

 Bosutinib 47%; imatinib 37% (P = 0.0200)

CCyR at 12 months:

 Bosutinib 77%; imatinib 66% (P = 0.0075)

Grade ≥ 3 vascular events by 18 months:

 Bosutinib 2%; imatinib 0%

Most common grade ≥ 3 non-hematologic TEAEs:

 Increased alanine transaminase: bosutinib 21%; imatinib 2%

 Increased aspartate aminotransferase: bosutinib 10%; imatinib 2%

Bosutinib discontinuation at 12 months (n = 59/268, 22%):

 AEs (n = 37, 14%)

 Patient request (n = 6, 2%)

Imatinib discontinuations at 12 months (n = 71/265, 27%):

 AEs (n = 24, 9%)

 Suboptimal response/treatment failure (n = 16, 6%)

Nilotinib and dasatinib. JALSG CML212 (#UMIN000007909) [104]: phase 3, randomized, open-label, multicenter trial of achievement of MR^4.5 after treatment with nilotinib versus dasatinib

Newly diagnosed CML-CP confirmed by cytogenetic study and/or detection of BCR::ABL1 by RT-PCR

Cumulative MR^4.5 rates at 18 months (primary endpoint):

 Nilotinib 33%; dasatinib 31%

Grade 3/4 AEs with ≥ 10% frequency nilotinib:

 Lipase elevation (12%)

Grade 3/4 AEs with ≥ 10% frequency dasatinib:

 Thrombocytopenia (17%)

 Neutropenia (13%)

Discontinued treatment by 18 months: 24% of nilotinib- and 20% of dasatinib-treated patients