ADC Reviews

Chronic myeloid leukemia (CML) targeted therapy

targeted therapy

Targeted therapy is to design a corresponding therapeutic drug at the cellular and molecular level, targeting a well-defined carcinogenic site (the site can be a protein molecule inside a tumor cell or a gene fragment), and the drug enters the body It will specifically select oncogenic sites to combine and act to cause the specific death of tumor cells without affecting the normal tissue cells around the tumor, so molecular targeted therapy is also known as “biological missiles”.

Drug introduction
According to the mechanism of action, the targeted therapy for CML is targeted therapy with kinase blockade (TKI). The commonly used drugs are imatinib, dasatinib and nilotinib, all of which are tyrosine kinase inhibitors. , inhibit the autophosphorylation and substrate phosphorylation of BCR-ABL protein by occupying the ATP binding site of BCR-ABL fusion protein, so that the proliferation or apoptosis of BCR-ABL positive cells is inhibited.

A generation of targeted therapy drugs
Indications: For the treatment of chronic myeloid leukemia (CML) in blast phase, accelerated phase, or chronic phase patients after failure of alpha-interferon therapy; patients with malignant gastrointestinal stromal tumors (GIST) that cannot be surgically removed or metastasized.
Efficacy: The results of the IRIS trial, an international large-scale clinical study, showed that the 8-year overall survival rate of imatinib in the treatment of patients with chronic CML was 85%, and the death rate related to CML was 7%. However, with the promotion of the drug’s clinical application, more and more cases appear to be resistant to imatinib. There are many mechanisms of resistance to imatinib, more than 50% of which are due to the mutation of one or more amino acids in the BCR-ABL fusion protein, which prevents imatinib from binding to the ATP-binding site of the fusion protein. Imatinib is the clinical first-line drug for the treatment of CML. With the emergence of imatinib resistance, the emergence of second-generation targeted therapy drugs, dasatinib and nilotinib, brings new hope to patients with chronic myeloid leukemia.

When to switch to second-generation drugs
When imatinib treatment fails, the first step is to evaluate compliance, consider mutation analysis, and evaluate drug interactions to adjust the treatment plan. At this time, it is possible to consider switching to a second-generation TKI. The earlier the switch, the greater the benefit.
The following indicators can be used to judge the failure of imatinib treatment:
1. March: Incomplete hematologic response (CHR)
2. June: Cytogenetic response (CyR) not reached
3. December: Partial cytogenetic response (PCyR) not obtained
4. 18 months: Complete cytogenetic response (CCyR) not obtained

Treat any period of time:
1. Hematologic recurrence (CHR loss)
2. Loss of Acquired Cytogenetic Response (CCyR)
3. The presence of BCR-ABL kinase mutations
4. Clonal chromosomal abnormalities other than Ph chromosomes
The 7-year follow-up data from the IRIS study showed that 18% of patients who received imatinib did not achieve a complete cytogenetic response (CCyR), 17% of patients who achieved CCyR lost their once achieved response, and 14% maintained Patients with CCyR did not achieve a major molecular response (MMR), and in total approximately 50% of patients did not achieve therapeutic goals, and this subset of patients was at higher risk of disease progression. Median survival is only 1-2 years if patients progress to accelerated/blastoid phase. The findings suggest that patients who do not meet their treatment goals are at risk for disease progression.
The proportion of suboptimal imatinib efficacy increased with treatment time, and suboptimal efficacy meant failure. Slow particle therapy requires three-month molecular remission of less than 10%, and if the long-term survival is more than 10%, there is a significant difference between patients with more than 10%. It turns out that when the efficacy of Gleevec is not good, the dose of Gleevec will be increased. For example, the original 400 mg will be increased to 600 mg. Generally, it is not recommended to increase the dose, but to change the medicine.

Early molecular response is critical when treating with imatinib. Many studies have confirmed that: after 3 months of imatinib treatment, patients with BCR-ABL molecular level >10% have poor prognosis, and it is recommended to switch to second-generation TKI therapy in time. 3 months is an important evaluation time, very important for predicting efficacy, and may be an important node for dressing change.

Choice of second-generation drugs
There are two types of second-generation TKI drugs, dasatinib (Sdazai) and nilotinib (Dashina). Which drug should be selected should consider factors such as efficacy, safety, mechanism of action, compliance, and indications.

Curative effect
When the first-generation TKI was not effective, switching to dasatinib, the 48-month progression-free survival rate reached 63%; switching to nilotinib, the 48-month progression-free survival rate reached 57%. Nilotinib is better.
One of the advantages of dasatinib is that it has a unique molecular structure, so the dose of dasatinib required to reduce BCR-ABL by half is only 1.8nM, and the drug effect is relatively strong; and nilotinib Nitrate was modified from the parent structure of imatinib, and the dose that reduced BCR-ABL in half was 20 nM.

In addition, dasatinib has a dual effect, inhibiting BCR-ABL and inhibiting SRC family kinases. Nilotinib is insensitive to SRC family kinases and cannot inhibit SRC family kinases.
In addition, dasatinib can pass through the blood-brain barrier. Many chemotherapy drugs cannot pass through the blood-brain barrier. The blood-brain barrier is like a wall, and only certain drugs can pass through. If there are some leukemia cells in the brain, it will take a period of time. From two to two, two to four, to a certain extent, symptoms appear, so it is difficult to deal with leukemia in the brain. But one of the benefits of dasatinib is that it can pass through the blood-brain barrier and can clear leukemia in the brain. This is a very important role of dasatinib. There is no data on whether nilotinib can cross the blood-brain barrier.

Nilotinib is twice a day. Due to the influence of food on blood concentration, it is necessary to take the medicine 2 hours before meals and 1 hour after meals, and the interval is 12 hours, or three times a day every eight hours. Hours, even dosing, taking medicine and meals should be separated. But Dasatinib has nothing to do with whether you eat or not. It is more convenient and simple to take once a day.
Indications: Compare therapeutic ranges
Dasatinib can be used in chronic phase, accelerated phase and blast phase, nilotinib is only used in chronic phase and accelerated phase.

Adverse reactions
It is very important to find the treatment of adverse reactions, which also improves the effect of our treatment. Timely treatment of adverse reactions can improve the curative effect and improve the quality of life. The main adverse reactions of nilotinib are blood count, pancytopenia, constipation, rash, nausea, back pain, fever, muscle cramps, headache, weakness, itching, hair loss, fatigue, increased bilirubin, cough, Stomach pain, the frequency is probably more than 10%. Liver function must be checked for nilotinib.

The side effects of dasatinib also include gastrointestinal reactions, diarrhea, fatigue, vomiting, and edema of dasatinib, but overall it is well tolerated. The adverse reactions mostly occur in the early stage and are of mild grade, such as pleural effusion. Easy to manage.