Table 3.

Efficacy and safety results from prospective clinical trials of TKIs in the 3L

Trial	Efficacy	Safety
A phase I/II trial of 3L + bosutinib in patients with CML-CP resistant/intolerant to imatinib + dasatinib and/or nilotinib   (Study 200) [18]	At 4 years:  74% cumulative cCHR   63% probability of maintaining cCHR  40% cumulative MCyR   69% probability of maintaining MCyR  24% cumulative incidence of on-treatment CML-AP/BC or death and 22% on-study deaths  78% KM-estimated OS	TEAEs reported in 100% of patients and grade 3/4 TEAEs reported in 68.1% of patients Most common TEAEs were diarrhea (83%), nausea (48%), vomiting (38%), and thrombocytopenia (39%)
Ponatinib efficacy and safety in Ph + leukemia [19, 46]	Overall, in patients with CML-CP [19]:  60% achieved MCyR at any time, of whom 54% achieved CCyR  40% achieved MMR  24% achieved MR4.5  3% of patients transformed to CML-AP/BC  KM-estimated PFS and OS at 5 years was 53% and 73%, respectively In a study of patients with CML-CP and resistance/intolerance to nilotinib or dasatinib or who had a T315I mutation [46]:  51% of patients with intolerance/resistance and 70% with T315I mutation achieved MCyR, with 40% and 66% achieving CCyR, respectively  MMR was achieved in 27% of patients with resistance/intolerance to nilotinib or dasatinib and 56% of patients with a T315I mutation  12% of patients discontinue use due to AEs	In patients with CML-CP [19]:  Most common TEAEs  (≥ 40%) were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%)  Most common grade 3/4 TEAEs (≥ 10%) were thrombocytopenia (35%), neutropenia (17%), hypertension (14%), increased lipase (13%), abdominal pain (10%), and anemia (10%)  31% of patients had AOEs In a study of patients with CML-CP and resistance/intolerance to nilotinib or dasatinib or who had a T315I mutation [46]:  Common AEs were thrombocytopenia (37%), rash (34%), dry skin (32%), and abdominal pain (22%)  Serious arterial thrombotic events occurred in 9% of patients, with 3% considered to be treatment related  12% of patients discontinued use because of AEs

3L third line, AE adverse event, AOE arterio-occlusive event, cCHR cumulative confirmed complete hematologic response, CCyR complete cytogenetic response, CML-AP chronic myeloid leukemia in acute phase, CML-BC chronic myeloid leukemia in blast crisis, CML-CP chronic myeloid leukemia in chronic phase, KM Kaplan–Meier, MCyR major cytogenetic response, MMR major molecular response, MR^4.5 4.5-log molecular response (BCR-ABL1^IS ≤ 0.0032%), OS overall survival, Ph+ Philadelphia chromosome positive, PFS progression-free survival, TEAE treatment-emergent adverse event, TKI tyrosine kinase inhibitor