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In the past two decades, nearly 10 drugs at home and abroad have been approved for the treatment of chronic myelogenous leukemia, including imatinib, dasatinib, nilotinib, bosutinib and Ponatinib. Patients are more selective, but the question arises: Has the patient-centered survival benefit really improved? How can I optimize my drug sequencing strategy? Which first- and second-line agents work best? In this paper, the efficacy and safety of several drugs currently used for the clinical treatment of CML are reviewed and analyzed. It is hoped that it will provide certain reference value for the drug selection of clinical treatment of CML.
1
Chronic myelogenous leukemia and its pathogenesis
Chronic myelogenous leukemia (CML) is a clonal pluripotent hematopoietic stem cell proliferative malignancy. The incidence of CML in the country is 0.36/10000, mostly in middle-aged people, with a male-to-female ratio of 16:1. The course of the disease is generally divided into: chronic phase (CP), accelerated phase (AP), and blast phase (BP). At present, scholars at home and abroad believe that its main pathogenesis is that the Abl gene on the long arm of chromosome 9 (9q34) and the Bcr gene on the long arm of chromosome 22 (22q11) are ectopic, forming a shorter than normal chromosome 22, that is, t(9;22)q(34;11), called Philadelphia chromosome (Ph). The Bcr-Abl fusion gene on this abnormal chromosome is the molecular basis of pathogenicity, and the coding product of this gene has strong tyrosine kinase activity, phosphorylation of a large number of substrates, activation of downstream signaling pathways, interference with a series of cell proliferation, apoptosis and adhesion signals of hematopoietic stem cells, resulting in excessive proliferation of blood cells, obstruction of apoptosis and premature release of immature cells into peripheral blood, which in turn causes the occurrence of CML[1].
2
Treatment options for chronic myelogenous leukemia
Patients with CML are mostly relieved by traditional treatments such as chemotherapy, interferon α therapy, and allogeneic stem cell transplantation, but rarely achieve major molecular remission (MMR). In 2001, a small molecule tyrosine kinase inhibitor (TKI) targeting the molecular pathogenesis of CML, imatinib mesylate, was first reported, bringing the treatment of CML into the molecularly targeted therapy stage. Currently, the drug of choice for the treatment of CML is tyrosine kinase inhibitors (TKIs). First-line drugs that have been marketed for the treatment of CML-CP are imatinib, dasatinib, nilotinib, bosutinib, and Ponatinib, of which imatinib and second-generation TKIs are mainly used in the treatment of patients in the initial stages. In 2012, the U.S. FDA approved bosultenib and others for use in patients with refractory CML [2].
1. Imatinib first-line treatment CML
Imatinib is aniline class Bcr-Abl TKI. In 2001, the U.S. FDA approved imatinib for the treatment of patients with CML in CP and BP after interferon α treatment failure, and it was the first TKI approved for the treatment of CML. In December 2002, imatinib was approved as a first-line treatment drug for patients with cmL, which can block the binding of adenosine phosphate (ATP) to the catalytic central site of Bcr-Abl tyrosine kinase, competitively inhibit Bcr-Abl self-phosphorylation and substrate phosphorylation, that is, at the level of signal transduction pathway, to achieve the purpose of inhibiting cell proliferation and inducing apoptosis, playing a role in the treatment of CML.
1.1 Standard dose
Imatinib is the first-line agent for the treatment of CML-CP, and the recommended dose for adults is 400 mg/day. Before the advent of the second-generation TKIs, for patients with CML-CP who failed treatment with standard doses of imatinib, the patient's condition was clinically relieved by increasing the dose of imatinib to 600 mg or 800 mg. In particular, patients with failed cytogenetic remissions can achieve higher complete cytogenetic remissions (CCyR) with increased doses, but toxicity has also increased accordingly. The recommended dose for children is 300 mg/m2 and the maximum dose for use is 400 mg. Imatinib can sometimes cause gastrointestinal inflammation. Imatinib should be taken with food and a large glass of water to reduce gastrointestinal adverse reactions.
1.2 Effectiveness and Safety
In the IRIS (International Randomized Study of Interferon and STI571) trial, imatinib established the "gold standard" as the initial treatment for CML. Fifteen untreated patients with CML-CP were randomized to receive a combination of interferon α and low-dose cytarabine (IFN-α/Ara-C) or imatinib at 400 mg/day alone. After 19 months, it was found that the therapeutic effect of imatinib was significantly better than that of ifN-α/Ara-C combination, and the CCyR rate of Imatinib treatment group reached 76.2%, while the CCy R rate of IFN-α/Ara-C treatment group was only 14.5% (P<0.001). Only 14.3 percent of patients in the imatinib treatment group discontinued treatment or switched to other treatments due to treatment failure or excessive side effects, compared with 89.2 percent of patients treated with an IFN-α/Ara-C combination who discontinued treatment and switched to imatinib due to treatment failure or excessive side effects [3].
Another clinical trial has investigated the therapeutic effects of imatinib at standard doses and high doses. The study selected 476 patients for optimal and selective studies of the drug. In the first 6 months, the CCyR and MMR rates in the high-dose imatinib-using group were significantly better than those in the standard-dose group; however, after 12 months, there was no significant difference in the CCyR rate and MMR rate between the two groups. Similarly, the same was shown in a Phase IV clinical trial of CML in Germany, where the clinical advantage of high-dose (800 mg) imatinib was no longer evident after 12 months of use compared to standard doses (400 mg).
These results suggest that high doses of imatinib may have some effect in the initial treatment of CML before the emergence of second-generation TKI. Although the incidence of side effects has increased at high doses of imatinib, proper tracking and management of side effects may go some way to ensuring the safety of patients who are in dire need of treatment with high-dose imatinib.
1.4 Contraindications to drugs
People who are allergic to the drug are contraindicated and pregnant women should avoid using the drug. Patients with heart failure and eosinophilic myocarditis should be monitored when using the drug.
2. Dasatinib - the second generation of TKI drugs came out
Dasatinib is the first second-generation TKI for Bcr-Abl resistance, belonging to the thiazole carboxylamide class, which can bind to the ATP binding site of the Bcr-Abl fusion gene in the activated or inactive state, inhibit the self-phosphorylation of the protein and the phosphorylation of the substrate, and inhibit the proliferation of Ph(+) cells or apoptosis. Its in vitro inhibitory activity is more than 300 times that of imatinib, which inhibits most of the Bcr-Abl variants that are resistant to imatinib, but is ineffective against T315I variants, F317V/L variants, and some rare clinical variants, such as T315A, V299L, etc. [5].
2.1 Standard dose
Due to the short half-life of dasatinib, the initially approved dose was 2 times a day. However, clinical studies have found that a dose of 1 dose per day helps to reduce the toxicity of the drug, especially fluid retention and bone marrow suppression, while the therapeutic effect is almost unchanged. The recommended dose of dasatinib as a treatment for CML-CP is 100 mg/day for adults, 140 mg/day for patients with no significant effect, and 140 mg/day for advanced CML. Dasatinib is administered in oral form, and grapefruit juice foods are contraindicated during the administration.
2.2 Effectiveness and Safety
Dasatinib was approved by the U.S. FDA in 2006 for the treatment of CML-CP, AP, and BP patients who cannot tolerate imatinib or are resistant to imatinib. Different randomized trials of single drugs have shown that dasatinib enables patients to obtain better CCyR and MMR. In one active study trial, the efficacy of dasatinib at 70 mg twice daily with 800 mg of high-dose imatinib therapy in 150 CML-AP patients (resistant to imatinib) was compared. After 6 years of clinical trials, it was found that the efficacy of dasatinib was significantly better than that of imatinib.
In a Phase III clinical trial, 519 newly confirmed PATIENTS WITH CML-CP were compared with the efficacy of dasatinib 100 mg/day versus imatinib 400 mg/day. Clinical data after 12 months showed that the therapeutic effect of dasatinib was significantly better than that of imatinib [CCyR rate (77% vs. 66%, P<0.007), MMR rate (46% vs. 28%, P<0.0001)]. In terms of safety, both have some degree of bone marrow suppression and pleural effusion, but in terms of other side effects, the incidence of dasatinib is lower than that of imatinib, such as muscle spasm, bone marrow suppression, gastrointestinal bleeding, etc. A recently reported 2-year clinical data showed that dasatinib and imatinib had similar CCyR rates (86% vs 82%). However, dasatinib showed a deeper MMR rate (17% vs. 8％）。 Patients using dasatinib also had a faster therapeutic effect than imatinib, and the conversion rate from CP to AP and BP was also slower than that of imatinib. Another 36-month clinical data showed that the CCyR rate and MMR rate of dasatinib were 78% and 76%, respectively, while the CCyR rate and MMR rate of imatinib were 58% and 44%, respectively.
2.3 Contraindications to drugs
People who are allergic to the drug are contraindicated and should be avoided in combination with antiplatelet drugs.
3 Bosultenib – a second-generation TKI inhibitor
Bossuvinib is a second-generation TKI inhibitor. It inhibits most Imatinib-resistant Bcr-Abl mutations except T315I and V299L mutations.
3.1 Standard dose
Bosutinib was approved by the U.S. FDA in 2012 for use in patients with CML who had become resistant or tolerated prior treatments. The recommended dose for adults is 500 mg once daily. For patients with severe drug resistance, the dose can be appropriately increased to 600 mg/day. Bosutinib tablets are administered orally.
3.2 Effectiveness and Safety
In a recently reported phase I/II clinical trial of bosutinib, 288 patients with CML-CP who were intolerant to imatinib (n=88) or drug-resistant (n=200) were given a regimen of bosutinib. After 2 years, 53% of patients received MCyR and 41% of patients, with 2-year progression-free survival and overall survival of 79% and 92%, respectively. After 28.5 months of treatment with bosutinib in 118 CML patients who failed treatment with imatinib, nilotinib, and dasatinib, 32% of patients received MCyR and 24% of patients received CCyR. Bossultinib is equally effective for a variety of Abl mutations caused after treatment with dasatinib and nilotinib [6]. In a Phase III clinical trial, 502 newly confirmed patients with CML-CP were clinically tested at a dose of 500 mg/day (n=250) for bosutinib and 400 mg/day (n=252) for the control imatinib. After 12 months, the CCy R rates were closer (70 vs.68 percent); however, the MMR rate for bosutinib was 41 percent compared to 27 percent for imatinib; and the conversion rate of patients treated with bosutinib to AP or BP was smaller (2 percent versus 4 percent) than imatinib [7].
3.3 Contraindications to drugs
People who are allergic to this product should contraindicate the drug. Pregnant and lactating women should avoid using this drug.
Comparison of advantages and disadvantages of imatinib, dasatinib and bosotinib
TKIs targeting the Bcr-Abl fusion gene have been hugely successful in treating CML. However, in the process of drug treatment, drug-resistant mutations will inevitably occur, and they all have different degrees of toxic side effects. Imatinib, the representative drug of the first generation of TKI, has a good effect on initial patients who have not been treated with other TKIs, but patients are prone to bcr-Abl gene mutations after medication, resulting in intolerance or resistance. The second generation of TKIs dasatinib and bosutinib are effective for most Bcr-Abl gene mutations, and have a good therapeutic effect on patients with imatinib intolerance or drug resistance, but they are ineffective against T315I mutations. In addition, the non-tyrosine kinase inhibitor homotricillin is mainly used in patients with refractory CML. Therefore, in clinical treatment, according to the stage of development of the patient's condition, the drug use, drug resistance, and the efficacy and toxic side effects of the drug itself, the drug itself should be comprehensively evaluated, and the drug should be reasonably selected for treatment, so as to give full play to the drug efficacy and improve the safety of drug use.
3
Prospects for CML treatment of chronic myelogenous leukemia
It is currently thought that allogeneic hematopoietic stem cell transplantation (HSCT) remains the only possible cure for CML. Because CML patients are predominantly elderly, they often have concomitant diseases. As a result, the application of HSCT in CML brings certain limitations. With the deepening of people's understanding of the abnormal methylation status of tumors, further research on the pathogenesis of CML, and the exploration of potential targets of CML by second-generation sequencing technology, clinical research on new drugs continues to emerge, and it is believed that in the near future, the efficacy and survival of CML patients will be significantly improved.
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