China
Africa
Explore chapters and articles related to this topic
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
As a “dual kinase inhibitor” bosutinib inhibits the autophosphorylation of both the Abl and Src kinases, resulting in inhibition of cell growth and apoptosis. Through this dual mechanism of action it is active in other myeloid malignancies and solid tumors in addition to resistant CML. Furthermore, it causes fewer side effects compared to earlier generations of compounds of this class because it more selectively inhibits the mutated proteins in leukemic cells with minimal effect on similar proteins in normal cells.
Overview of Therapeutic Biomarkers in Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Sherry X. Yang, Janet E. Dancey Treatment
In nearly two decades, several classes of the small-molecule kinase inhibitors have become effective treatment for cancer patients whose tumors harbor genetic aberrations such as gene mutation, amplification or chromosomal translocation in the target kinases. The fusion gene of the c-ABL proto-oncogene from chromosome 9 with the breakpoint duster region (BCR) on chromosome 22 (BCR-ABL fusion gene on chromosome 22) is referred to as the Philadelphia chromosome (Ph+). It encodes a constitutively active tyrosine kinase in chronic myelogenous leukemia (CML), some acute lymphoblastic leukemia, and acute myelogenous leukemia (Chapter 8). Patients with Ph+ disease respond to a class of the tyrosine kinase inhibitors (TKIs) targeting BCR-ABL such as imatinib, dasatinib or nilotinib. In addition, the FDA approved bosutinib and ponatinib to treat adult patients with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Following the identification of resistance to imatinib, three oral second-generation TKIs, dasatinib, nilotinib, and bosutinib, entered clinical trials in 2006. Dasatinib and bosutinib are dual SRC-ABL1 kinase inhibitors given once daily, and nilotinib was developed from imatinib by crystallographic analysis of compounds binding to imatinib-resistant BCR-ABL1 mutants. Randomized studies showed increased benefits compared with imatinib in terms of the speed of achieving DMR in a higher proportion of patients and a reduction in the incidence of transformation to advanced phases, which was not significant; at present, there is no improvement in OS. The discontinuation rates for the drugs were about 30% at 2 years, largely due to side effects. Dasatinib was associated with myelosuppression, pleural effusions, and infrequently, pulmonary arterial hypertension and hemorrhagic colitis.73 Bosutinib was associated with diarrhea, hepatotoxicity, and anaphylactic shock.74 Nilotinib was associated with increased risk of peripheral arterial occlusive disease and metabolic effects, such as hyperglycemia, elevated cholesterol, and elevated lipase with frank pancreatitis.75 It has a black box warning for QTc prolongation and cardiac death.
Managing women of childbearing age with chronic myeloid leukemia: safety and treatment considerations
Published in Expert Review of Hematology, 2023
HF Robertson, MJ Buckton, JF Apperley
There is very little information reporting the safety profile of bosutinib in pregnancy. The largest study to date was from Cortes et al., who described at 16 pregnancies in females receiving bosutinib, only ten of whom had known outcomes [50]. Six pregnancies resulted in live births (five of which were live normal healthy children, the outcome of the other was unknown) and the remaining four patients had terminations. Three of these terminations were elective: two were by patient choice and one due to a molar pregnancy. The one spontaneous termination was due to an ectopic pregnancy that was deemed by the study coordinators to be unrelated to bosutinib. The lack of in-human evidence combined with fetal toxicity in preclinical testing means bosutinib is not advised during pregnancy [42].
Ponatinib for the treatment of adult patients with resistant or intolerant Chronic-Phase Chronic Myeloid Leukemia
Published in Expert Opinion on Pharmacotherapy, 2022
Fadi G. Haddad, Ghayas C. Issa, Elias Jabbour, Musa Yilmaz
In October 2021, asciminib was approved for CP-CML patients previously treated with 2 or more TKIs. The approval was based on the results of the ASCEMBL phase III randomized trial comparing asciminib to bosutinib. A total of 233 patients with CP-CML were randomized (2:1) to receive asciminib 40 mg twice daily or bosutinib 500 mg once daily, with a primary objective of 6-month MMR rate [45]. The most recent update reported the outcome of patients after a median follow-up of 19.2 months [46]. The cumulative MMR rates at 12 months were 33.2% and 18.6% with asciminib and bosutinib, respectively. The CCyR rate at 12 months in patients without CCyR at baseline was 50.8% with asciminib compared with 33.7% with bosutinib. With this longer follow-up, the differences in deep molecular responses were in favor of asciminib over bosutinib, with MR4 and MR4.5 rates of 14.0% and 9.6% compared with 6.6% and 2.6%, respectively. Grade ≥3 side effects were reported in 54.5% and 67.1% of patients treated with asciminib and bosutinib, respectively [46]. The rate of bosutinib discontinuation on this trial was 77.6%, which is higher than the rate of 20% reported with the initial trial of bosutinib in CML patients resistant or intolerant to prior TKIs [47].
Current status of drug repositioning in hematology
Published in Expert Review of Hematology, 2021
Bosutinib is a second-generation TKI approved for the treatment of CML. A phase III trial of bosutinib and imatinib for patients with newly diagnosed CML demonstrated that the bosutinib group had higher rates of a major molecular response (47% vs. 37%, P = 0 · 02) and a complete cytogenetic response (77% vs. 66%, P = 0 · 008) at 12 months after treatment initiation [44]. In terms of action mechanisms, bosutinib selectively inhibits Bcr-Abl TK and Src-family kinase [45]. Using motor neurons generated from induced pluripotent stem cells (iPSCs), Imamura et al. revealed that the Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis (ALS), and bosutinib is a promising agent for ALS management [46]. By screening 1416 drugs on the market or under investigation, they identified 27 compounds with motor neuron–protective effects, including 14 associated with the Src/c-Abl pathway. Of the 14 compounds, bosutinib exhibited a dose-dependent effect at a lower dose than did the other Src/c-Abl inhibitors. In their models, bosutinib prolonged the survival of ALS iPSC-derived motor neurons, where it reduced the amount of misfolded mutant superoxide dismutase 1 (SOD1) protein and attenuated the altered expression of mitochondrial genes. Currently, phase I study of bosutinib in patients with ALS is underway in Japan (UMIN 000036295).