Table 1.

TKIs used for the treatment of patients with CP-CML: overview of US prescribing information*

TKI	Mechanism of action	Indications in adults with CP-CML (as of September 2018)	Most frequently reported AEs	Warnings and precautions
Bosutinib [1]	• Inhibits BCR-ABL1 and SRC family (including SRC, LYN, and HCK) kinases	• 1L • ≥ 2L in patients with resistance or intolerance to prior therapy	• Incidence ≥ 20%: diarrhea, nausea, thrombocytopenia, rash, vomiting, abdominal pain, anemia, pyrexia, liver test abnormalities, fatigue, cough, headache, and edema	• No black-box warnings • Fetal harm • GI toxicity: diarrhea, nausea, vomiting, abdominal pain • Myelosuppression: thrombocytopenia, anemia, neutropenia • Hepatic toxicity: one case of drug-induced liver injury (defined as concurrent elevations in ALT or AST ≥ 3 × ULN with total bilirubin > 2 × ULN and alkaline phosphatase < 2 × ULN) • Fluid retention: may manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema • Renal toxicity: decline in estimated glomerular filtration rate
Dasatinib [16]	• Inhibits BCR-ABL1, SRC family (SRC, LCK, YES, and FYN), c-KIT, ephrin (EPH) receptor A2, PDGFRβ kinases	• 1L • ≥ 2L in patients with resistance or intolerance to prior therapy	• Incidence ≥ 15%: myelosuppression, fluid retention events (with pleural effusion occurring in 28% during long-term follow-up), diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain	• No black-box warnings • Fetal harm • Myelosuppression: thrombocytopenia, neutropenia, anemia • Bleeding-related events (mostly associated with severe thrombocytopenia): central nervous system, GI hemorrhages • Fluid retention: sometimes severe, including pleural effusions • QT prolongation • Cardiac dysfunction, including ischemic events, cardiac-related fluid retention, arrhythmia, and palpitations • Pulmonary arterial hypertension • Severe dermatologic reactions • Tumor lysis syndrome
Imatinib [14]	• Inhibits BCR-ABL1, stem cell factor, c-KIT, PDGFR kinases	• 1L (follow-up limited to 5 years) • ≥ 2L after failure of interferon-alpha therapy	• Incidence ≥ 30%: edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, abdominal pain	• No black-box warnings • Fetal harm • Edema and severe fluid retention • Anemia, neutropenia, thrombocytopenia • Severe congestive heart failure, LV dysfunction • Severe hepatotoxicity • Grade 3/4 hemorrhage and GI perforations • Cardiogenic shock/LV dysfunction in patients with conditions associated with high eosinophil levels • Bullous dermatologic reactions • Hypothyroidism • Tumor lysis syndrome • Renal toxicity • Motor vehicle accidents
Nilotinib [15]	• Inhibits BCR-ABL1, PDGFR, c-KIT, colony stimulating factor-1 receptor, discoidin domain receptor-1 kinases	• 1L • ≥ 2L in patients with resistance or intolerance to prior therapy that included imatinib	• Incidence ≥ 20% (non-hematologic): nausea, rash, headache, fatigue, pruritus, vomiting, diarrhea, cough, constipation, arthralgia, nasopharyngitis, pyrexia, night sweats • Most common hematologic: thrombocytopenia, neutropenia, anemia	• Black-box warning for QT prolongation and sudden death. Do not administer in patients with hypokalemia, hypomagnesemia, or long QT syndrome; avoid concomitant drugs known to prolong QT interval and strong CYP3A4 inhibitors; avoid food 2 h before and 1 h after dose • Fetal harm • Myelosuppression: neutropenia, thrombocytopenia, anemia • Cardiac and arterial vascular occlusive events • Pancreatitis, elevated serum lipase • Hepatotoxicity: elevations in bilirubin, AST/ALT, alkaline phosphatase • Electrolyte abnormalities: hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, hyponatremia • Tumor lysis syndrome • Hemorrhage • Total gastrectomy (removal of the entire stomach) • Fluid retention: pericardial effusion, pleural effusion, severe fluid retention • Treatment discontinuation; monitor frequently for typical BCR-ABL transcripts
Ponatinib [17]	• Inhibits ABL and T315I mutant ABL, SRC family, KIT, RET, TIE2, FLT3, VEGF receptor, PDGFR, fibroblast growth factor receptor, EPH receptor kinases	• ≥ 2L in patients for whom no other TKI therapy is indicated • ≥ 2L in patients with T315I mutation [18]	• Incidence ≥ 20% (non-hematologic): abdominal pain, rash, constipation, headache, dry skin, arterial occlusion, fatigue, hypertension, pyrexia, arthralgia, nausea, diarrhea, lipase increased, vomiting, myalgia, and pain in extremity • Most common hematologic: thrombocytopenia, anemia, neutropenia, lymphopenia, leukopenia	• Black-box warning for arterial occlusion, venous thromboembolism, heart failure, and hepatotoxicity (including liver failure and death) • Fetal harm • Hypertension • Pancreatitis • Neuropathy (peripheral and cranial) • Hemorrhage (cerebral and GI) • Ocular toxicity • Fluid retention: peripheral edema, pleural effusion, pericardial effusion, and peripheral swelling • Cardiac arrhythmias • Myelosuppression: thrombocytopenia, neutropenia, anemia • Tumor lysis syndrome • Reversible posterior leukoencephalopathy syndrome • Compromised wound healing and GI perforation

*Based on the current USA labels, for consistency as an overview

Abbreviations: 1L first-line, 2L second-line, AE adverse event, ALT alanine aminotransferase, AST aspartate aminotransferase, CP chronic-phase, CML chronic myeloid leukemia; CYP cytochrome P450, EPH ephrin receptor, GI gastrointestinal, LV left ventricular, MI myocardial infarction, PDGFR platelet-derived growth factor receptor, TKI tyrosine kinase inhibitor, ULN upper limit of normal, VEGF vascular endothelial growth factor