On November 9, 2017, the U.S. Food and Drug Administration (FDA) approved an “old drug” – the second-generation tyrosine kinase inhibitor ( tyrosine kinase inhibitor (TKI) dasatinib (trade name: Stacy, manufactured by Bristol-Myers Squibb) for the treatment of Philadelphia chromosome-positive (Ph+) children with chronic myelogenous leukemia (chronic myelogenous leukemia) in the chronic phase of the disease (early stage of the disease). chronic myelogenous leukemia (CML).
Dasatinib received accelerated marketing approval from the FDA in 2006 for the treatment of adult patients with Ph+ chronic-phase chronic myelogenous leukemia who are resistant or intolerant to treatment including imatinib. In addition, the FDA also approved treatment for adult patients with acute lymphoblastic leukemia (ALL) in Ph+. In 2010, dasatinib received accelerated FDA approval again for the treatment of adult patients with newly diagnosed chronic-phase Ph+ chronic granulocytic leukemia.
This approval demonstrates that dasatinib is also effective and safe in children with chronic-phase Ph+ chronic granulocytic leukemia.
What is chronic granulocytic leukemia?
Chronic granulocytic leukemia is a malignant clonal disease of hematopoietic stem cell origin that is associated with the production of BCR-ABL fusion genes due to translocations of the Ph chromosome (Philadelphia chromosome) caused by radiation and chemotherapeutic agents (e.g., alkylating agents, anthracycline antibiotics, etc.).
Chronic granulocytic leukemia can be divided into a chronic phase, an accelerated phase, and an acute phase. Patients with chronic phase chronic granulocytic leukemia have primitive cells in the peripheral blood or bone marrow<10%.
Chronic granulocytic leukemia accounts for less than 3% of new pediatric leukemia diagnoses, but it is often more aggressive and has limited treatment options compared with adult patients. Because of the small number of patients with the disease, clinical trials in children with chronic granulocytic leukemia are usually fewer, which further limits treatment options for this group of children.
How does dasatinib work?
The vast majority of chronic granulocytic leukemia is caused by chromosome Ph, an abnormal chromosome discovered in 1960 and named after Philadelphia, where it was discovered. It was created when chromosome 9 and chromosome 22 broke and swapped places. This change led to the production of a fusion protein called BCR-ABL, which acts as a tyrosine kinase and directly causes the uncontrolled growth of white blood cells in the human bone marrow, which continue to accumulate in the bloodstream and proliferate indefinitely. The long-established targeted drug Imatinib (trade name: Gleevec, manufactured by Novartis) is a highly selective inhibitor of BCR-ABL.
Dasatinib, similar to imatinib, also inhibits BCR-ABL. because structurally different from imatinib, dasatinib binds to ABL in an activated conformation that inhibits not only ABL kinases, but also Src family (SRC, LCK, YES, FYN) kinases, as well as c-KIT, EPHA2, and PDGFRβ, dasatinib is highly selective for BCR- ABL fusion gene-positive cell lines 100-300-fold more strongly than imatinib, and 1000-fold more strongly than imatinib in reducing BCR-ABL phosphorylation activity. And dasatinib may be effective in patients who are resistant to imatinib.
Evidence of efficacy: >95% complete remission rate, rapid onset of action, and increased benefit with longer dosing
The approval of dasatinib was based primarily on the results of 2 early clinical trials (a phase I trial and a phase II trial).
After 1 year of treatment, 96.1% of 57 children initially diagnosed with chronic granulocytic leukemia achieved complete remission (complete disappearance of cancer cells); 82.6% of 46 children with chronic granulocytic leukemia who were intolerant of imatinib or resistant to imatinib achieved complete remission. Children with initial diagnosis were followed for an average of 4.5 years, and more than half did not experience disease progression.
Also, in the phase II trial, remission occurred soon after treatment, and the benefit to the children increased with longer treatment.
Adverse effects: alert for pulmonary hypertension
Common adverse reactions to dasatinib include headache, nausea, diarrhea, rash, vomiting, extremity pain, abdominal pain, fatigue, and joint pain. Dasatinib may also affect growth and development in children.
It is important to note that some patients may develop a rare but serious condition called pulmonary arterial hypertension (PAH) after taking dasatinib. If left untreated, pulmonary arterial hypertension can be fatal.
In addition, one of the typical adverse effects of dasatinib when treating adult patients with chronic granulocytic leukemia is pleural effusion, but this is hardly observed in children.
How do I use dasatinib?
According to the approved product insert, the recommended use and dosage of dasatinib is as follows:
- For children, the recommended dose of dasatinib is related to weight.
- 10 kg ≤ weight<20 kg, 40 mg orally daily;
- 20 kg≤weight<30 kg, 60 mg orally daily;
- 20 kg≤weight<30 kg, 60 mg orally daily;
- 30 kg ≤ body weight <45 kg, 70 mg orally daily;
- 30 kg ≤ body weight <45 kg, 70 mg orally daily;
- 100 mg orally per day for 45 kg≤bw. The dose needs to be recalculated every 3 months, or more frequently if necessary, depending on the child’s weight.
- Avoid concomitant use of strong CYP3A4 inhibitors, grapefruit juice, strong CYP3A4 inducers, and St. John’s wort (also known as onychomycetes, an herb) while taking this medication.
- For pediatric patients with chronic-phase chronic granulocytic leukemia, use of dasatinib until disease progression or unacceptable toxicity occurs, and dasatinib may cause a decrease in white blood cells and platelets, so regular follow-up monitoring is required while taking the drug.
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Dasatinib was approved by our Food and Drug Administration on September 8, 2011, for second-line treatment of chronic myeloid leukemia and has not yet been approved in China for children with chronic granulocytic leukemia, but the efficacy it has shown in studies has been encouraging, and as immunotherapy research deepens, more TKI’s targeting the Ph chromosome may be available in the future to better treat children with chronic granulocytic leukemia.