The incidence and natural history of dasatinib complications in the treatment of chronic myeloid leukemia

Abstract

Key Points• Prescribing appropriately for age and cardiovascular risk is likely to result in minimal permanent toxicity-related dasatinib cessation.• CML patients on dasatinib with pleural effusion are more likely to have achieved MR4.5 after 6-month therapy than those without effusion.Dasatinib has shown superiority over imatinib in achieving molecular responses (MRs) in chronic phase chronic myeloid leukemia but with a different toxicity profile, which may impact its overall benefit. Reported toxicities include pleural effusions and pulmonary hypertension, and although the incidence of these events is well described, response to therapy and impact of dose modifications on toxicity has not been comprehensively characterized in a real-world setting. We retrospectively reviewed the incidence of dasatinib adverse events in 212 chronic phase chronic myeloid leukemia patients at 17 Australian institutions. Adverse events were reported in 116 patients (55%), most commonly pleural effusions (53 patients, 25%), which was the predominant cause of permanent drug cessation.Age and dose were risk factors for pleural effusion (P , .01 and .047, respectively).Recurrence rates were higher in those who remained on 100 mg compared with those who dose reduced (P 5 .041); however, recurrence still occurred at 50 mg. Patients who developed pleural effusions were more likely to have achieved MR4.5 after 6 months of dasatinib than those without effusions (P 5 .008). Pulmonary hypertension occurred in 5% of patients, frequently in association with pleural effusion, and was reversible upon dasatinib cessation in 6 of 7 patients. Dose reductions and temporary cessations had minimal impact on MR rates. Our observations suggest that by using the lowest effective dose in older patients to minimize the effusion risk, dose modification for cytopenias, and care with concomitant antiplatelet therapy, the necessity for permanent dasatinib cessation due to toxicity is likely to be minimal in immunologically competent patients.

Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease

“…For example, D is usually administered continuously with a tolerable side effect profile at 100 mg/day (the dose used here for only a total of 3 days) for years or even over a decade in patients with chronic leukemias [61]. Most potential side-effects of D can be avoided though intermittent administration and, generally, serious side effects of D reverse upon temporary discontinuation [62,63], increasing the value of the opportunity to administer D intermittently, yet still benefit from its senolytic effects.…”

The natural history of vascular and other complications in patients treated with nilotinib for chronic myeloid leukemia

“…Seventeen institutions agreed to participate in a survey of CML patients treated with nilotinib and dasatinib; the dasatinib component of this survey has been published. 13 All eligible patients at each site were included in the study if they received nilotinib for CML-CP at any time between 1 February 2005 and 30 June 2015 and had sufficient clinical details available. A comprehensive medical record review was undertaken, with key data collected including sex, date of birth, starting dose and duration of nilotinib therapy, sequential BCR-ABL1 transcript levels, prior CML-CP therapy, reasons for and details of any dose modifications, including temporary or permanent cessation, and AEs of all grades (graded as per Common Terminology Criteria for Adverse Events version 4.0).…”

Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio‐Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio‐Oncology Society

“… Vascular endothelial growth factor (VEGF) inhibitors [these agents are also known as angiogenesis inhibitors or VEGF tyrosine kinase inhibitors (TKIs) as many act via multi‐targeted inhibition of tyrosine kinases] : the main CV complications of VEGF inhibitors are systemic hypertension, LVD and HF, QTc prolongation and arterial thrombosis including MI 48,53,57,72 Multi‐targeted kinase inhibitors for chronic myeloid leukaemia (CML) targeting BCR‐ABL (often called BCR‐ABL TKIs) : the main CV complications of multi‐targeted kinase inhibitors for CML targeting BCR‐ABL include arterial thrombosis leading to MI, stroke and peripheral arterial occlusive disease (ponatinib), venous thromboembolism, systemic hypertension, LVD and HF, accelerated atherosclerosis (ponatinib and nilotinib), QTc prolongation (nilotinib) and pulmonary hypertension (dasatinib) 59,62,73–78 Proteasome inhibitors (PIs) and immunomodulatory drugs (IMIDs) : the main CV complications of PIs and IMIDs in combination are LVD and HF, ischaemia and MI, atrial and ventricular arrhythmias, venous thromboembolism and arterial thrombosis 66,67,79 …”