On December 19, 2017, the U.S. Food and Drug Administration (FDA) expanded the indication for the targeted drug bosutinib (trade name Bosulif, manufactured by Pfizer Inc.). It is an oral drug, this time approved for the treatment of those newly diagnosed with chronic phase (CP) Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).
Bosutinib, a second-generation TKI drug, was first approved in 2012 for the treatment of patients with chronic myelogenous leukemia after prior TKI resistance. It is approved for the treatment of patients with Philadelphia chromosome-positive chronic granulocytic leukemia in the chronic, accelerated or acute phase who are resistant or intolerant to prior therapeutic agents. It is also indicated for the treatment of patients with primary Philadelphia chromosome-positive (Ph+) chronic granulocytic leukemia in the chronic phase. Bosutinib has a higher remission rate compared to conventional imatinib and is now a first-line drug for patients with Ph chromosome-positive chronic myeloid leukemia.
What is chronic granulocytic leukemia with Ph?
Chronic granulocytic leukemia is an abnormal, uncontrolled production of granulocytes by hematopoietic cells in the peripheral blood and bone marrow. Chronic myeloid leukemia can be divided into chronic phase, accelerated phase and acute phase. Chronic phase chronic granulocytic leukemia is characterized by primitive cells in the peripheral blood or bone marrow<10%. Chronic-phase chronic granulocytic leukemia develops into accelerated-phase chronic granulocytic leukemia after 3 to 5 years, or even less than 1 year. Accelerated-phase chronic granulocytic leukemia progresses to acute-phase chronic granulocytic leukemia in 6 months to 1 year. About 1/4 of patients may progress directly from the chronic phase to the acute phase without an accelerated phase.
More than 90% of patients with chronic granulocytic leukemia have a Ph chromosome mutation. This is due to an abnormal chromosome, the proto-oncogene BCR ABL chimerism, resulting from the fusion of the ABL tyrosine kinase gene on chromosome 9 with the BCR gene located on chromosome 22. This gene is directly associated with the development of chronic granulocytic leukemia.
What is bosutinib?
Bosutinib is a potent dual inhibitor of the protein kinase Src (sarcoma) and BCR ABL. src causes phosphorylation of the tissue surrounding the tumor, promoting tumor growth and metastasis. The BCR ABL fusion gene, on the other hand, activates tyrosine kinase and transplants cancer cell death. Bosutinib inhibits both the autonomous phosphorylation of Src proteins and the phosphorylation process of Src and BCR ABL substrates in a variety of human tumor cells as a way to exert anti-tumor effects.
Evidence of efficacy: 47.2% of patients achieved major molecular remission
Bosutinib was approved primarily based on a multicenter randomized controlled clinical trial (the BFORE study) enrolling 487 patients with newly diagnosed chronic-phase Ph+ chronic granulocytic leukemia randomized to receive 400 mg of bosutinib or 400 mg of imatinib, both once daily. The results of the study showed significantly better complete cytogenic response (CCyR) and major molecular response (MMR) at 12 months with bosutinib compared to imatinib (CCyR: 77.2% vs. 66.4%, MMR: 47.2% vs. MMR: 47.2% vs 36.9%).
The proportion of chronic granulocytic leukemia treated with complete genetic remission (defined as undetectable Ph+) is high, but complete genetic remission does not reflect the low level of residual disease in the body. Therefore, when assessing the efficacy of targeted agents such as imatinib, it is common to use, as a clinical endpoint, primary molecular biological remission. Major molecular biological remission is defined as ≤ international standard 0.1% BCR ABL (equivalent to a decrease of ≥3 log from baseline) and is a metric to assess molecular remission. Major molecular biological remission is usually detected by, for example, real-time PCR (RQ-PCR), which reflects the level of BCR-ABL transcripts. low levels of BCR-ABL transcripts put patients at low risk of relapse and longer disease-free survival (DFS).
Adverse effects: similar to those seen in previous treatments
Common adverse reactions to bosutinib include mainly diarrhea, abdominal pain, nausea, vomiting, thrombocytopenia, rash, anemia, fever, and fatigue.
In the treatment of newly diagnosed chronic phase Ph+ chronic granulocytic leukemia, the toxicity of bosutinib is similar to that seen in other treatments, mainly in the form of gastrointestinal toxicity, bone marrow transplantation, edema, and nephrotoxicity.
In addition, the drug should not be used during pregnancy and in women who are breastfeeding.
How do I use bosutinib?
According to the approved product insert, the recommended use and dosage of bosutinib is as follows:
The recommended use of bosutinib is as follows
- For newly diagnosed chronic phase Ph+ chronic granulocytic leukemia, the recommended dose is 400 mg orally daily.
- For newly diagnosed chronic phase Ph+ chronic granulocytic leukemia, the recommended dose is 400 mg orally daily.
- For patients who do not achieve hematologic, cytogenetic, or molecular remission and do not have more than grade 3 adverse events, the dose may be increased by 100 mg per day up to a maximum dose of 600 mg per day.
Bosutinib is not yet available in China, but the phase III clinical trial (CTR20132967) that included patients in China has been completed and is believed to be approved for marketing soon, providing an alternative treatment option to imatinib for patients with Ph+ chronic granulocytic leukemia.