Over the past 20 years, BCR/ABL1 tyrosine kinase inhibitors (TKI) have evolved rapidly and have greatly improved the treatment of Ph+ chronic granulocytic leukemia (CML) at all stages. Currently, there are 5 commonly used TKI in the clinic, namely imatinib, dasatinib, nilotinib, bosutinib and ponatinib. Since some CML patients need to take TKI for a long time, and long-term TKI treatment may have different adverse effects, the safety of treatment needs to be considered. In addition to this, as time passes, the disease may progress and relapse, and a series of complications may occur. Therefore, how to individualize the use of these drugs according to the actual situation has become a focus of clinicians’ attention.
Professor Larson from the University of Chicago has conducted a review on how to select TKI for the treatment of chronic-phase CML, and the relevant findings were published in a recent BLOOD, which you can take a look at.
Randomized Clinical Trials
There are a number of multicenter, randomized clinical trials of TKI therapy around the world. After the discovery that imatinib was more effective than recombinant interferon alpha and low-dose cytarabine, it was presented in all relevant studies as a standard control group, with a usage of 400 mg/day. There are no trials comparing the differences between second-generation TKI’s. Study primary endpoints: complete cytogenetic remission (CCyR), major molecular response (MMR), early molecular response (EMR), progression-free survival (PFS), and overall survival (OS).
Results of randomized clinical trials
1. Imatinib
Patients with newly diagnosed and untreated CML were divided into three groups and received 400 mg/day imatinib, 800 mg/day imatinib, or 400 mg/day imatinib combined with interferon or cytarabine for 12 years. 64% of patients remained on imatinib and 22% switched to a second-generation TKI. 5.6% of patients progressed to the acute phase (BC), with a PFS rate of 82% and an OS rate of 84% at 10 years. MMR was achieved in 89% of patients and MR was seen in 72% of patients, with better treatment outcomes in the imatinib 800 mg/day group. During the first 8 years of treatment, 76% of patients experienced adverse effects of varying severity, 22% experienced grade 3 or 4 adverse effects, 73% experienced non-hematologic adverse effects, and 28% experienced hematologic adverse effects.
2. Nilotinib
Patients with newly diagnosed chronic phase CML were randomized to three groups receiving nilotinib 300 mg/dose, BID, nilotinib 400 mg/dose, BID, and imatinib 400 mg/dose, QD. At 6 years of follow-up, cumulative MMR and MR were higher in the nilotinib group than in the imatinib group. After three months of treatment, more patients in the nilotinib group had BCR-ABL1 ≤ 1% than in the imatinib group, and fewer patients had BCR-ABL1 ≥ 10% than in the imatinib group. over 6 years, fewer patients in the nilotinib group progressed to accelerated (AP) or BC and fewer patients died of progressive CML than in the imatinib group. The OS rates were 91% in the imatinib group and 92% in the nilotinib 300 mg/dose, BID group, with no statistical difference between the two groups. Another study on nilotinib showed that at 12 months of treatment, the MMR rates were 52% and 28% in the nilotinib and imatinib groups, respectively. At 24 months of treatment, there was no difference in CCyR rates or PFS.
3. Dasatinib
At 5 years of follow-up, there was no difference in CCyR rates between the two groups, but the MMR and MR rates were higher in the dasatinib group than in the imatinib group, and the time to CCyR and MMR was shorter. The number of patients progressing to BC and AP was less in the dasatinib group than in the imatinib group, but there was no difference in the 5-year PFS and OS rates between the two groups. Patients who received dasatinib had a higher rate of EMR than imatinib, and those who obtained EMR within 3 months had better 5-year PFS, OS, and probability of progression to AP or BC than those who did not.
4. Bosutinib
Patients with newly diagnosed chronic-phase CML were randomized to two groups receiving prosutinib 500 mg/day and imatinib 400 mg/day, respectively. At 24 months of follow-up, there was no difference in cumulative CCyR rates between the two groups, and cumulative MMR rates were higher with bosutinib than with imatinib. 77% of patients in the bosutinib group and 84% of patients in the imatinib group continued treatment and maintained CCyR, and 82% of patients in the bosutinib group and 89% of patients in the imatinib group maintained MMR. In addition, better EMR was associated with higher CCyR and MMR rates.
5. Panatinib
Patients with newly diagnosed chronic-phase CML were randomized to two groups receiving ponatinib 45 mg/day and imatinib 400 mg/day, respectively. The duration of the study was short because patients in the ponatinib group developed thrombus in their arteries at an early stage. EMR, MR and MMR rates were higher in the ponatinib group than in the imatinib group, and ponatinib was more effective than imatinib in patients with newly diagnosed CML, but had a higher incidence of adverse events.
Early molecular reactions
Is there an early molecular response that predicts long-term disease prognosis? Researchers have found that when BCR/ABL1 transcript levels in peripheral blood cells decline rapidly, this tends to suggest higher MMR rates and better OS. it is unclear whether a change in treatment would achieve better treatment outcomes if EMR is not present.
In the TIDEL-II study, newly diagnosed patients were first treated with imatinib 600 mg/day, and those who failed to achieve the desired treatment effect at 3, 6, or 12 months were switched to imatinib 800 mg/day or nilotinib 400 mg/dose, BID. at 2 years of follow-up, 55% of patients remained on imatinib and 30% switched to nilotinib. at 3 years, the OS rate was 96% and 95% of patients had unconverted disease. Therefore, if the original treatment did not work, an early change in drug usage may be a good option.
Disease progression
Early in the study, there was concern that patients with CML would soon develop resistance to TKI and subsequent disease conversion to AP or BC, but in reality, disease conversion is less likely to occur if the disease is properly monitored. In most patients, MR becomes more intense as treatment progresses. Therefore, it is important to maintain a daily dose of therapy. If the dose of imatinib is reduced by 10%, the MMR rate decreases significantly. Most disease progression occurs within 2-3 years of TKI treatment. One study showed that over 6 years of treatment, the rate of disease progression was lower in the nilotinib 300 mg/dose, BID group than in the imatinib group, while the rate was lowest in the nilotinib 400 mg/dose, BID group. Another study showed that dasatinib had a lower rate of disease progression compared to imatinib. Genetic mutations are an important factor in disease progression and nilotinib is more effective in reducing mutation production compared to imatinib.
Discontinuation status
Some patients who maintain MR during the treatment phase may also maintain MR for a significant period of time after discontinuation; it is not known exactly what percentage of this population is involved, but it is clear that newly diagnosed patients in the chronic phase are not the majority of this population. The use of a more potent TKI at the beginning of treatment may improve the likelihood of maintaining MR after discontinuation.
Side effects
Serious side effects are rare with TKI use and are therefore often overlooked by clinicians. TKI may also exacerbate pre-existing conditions, and pre-existing conditions may also be a cause of death, so clinicians need to focus on CML as well as other conditions and individualize treatment accordingly.
Vascular toxicity
Studies have shown that nilotinib is more likely to produce vascular toxic events than imatinib, with ischemic heart disease, ischemic cerebrovascular disease, and peripheral arterial disease occurring primarily, and pleural effusion, pericardial effusion, and pulmonary edema less frequently. Patients treated with dasatinib have a higher incidence of pleural effusions, as well as arterial ischemic events, pulmonary hypertension, and adverse cardiovascular events. Panatinib promotes arterial thrombosis, and some patients also experience severe venous thromboembolic events.
Economic considerations
TKI drugs are expensive, which is often a reason why patients fail to adhere to their medications. Studies suggest that for newly diagnosed patients with chronic-phase CML, it is most cost-effective to start with the less expensive imatinib and, if treatment fails, switch to a more potent second-generation TKI.
Future treatment strategies
In the future, there will be two main aspects to consider: clinical and price. In addition to this, a combination of factors such as the patient’s tolerance to the drug, the presence of comorbidities and possible late complications and expected risks at diagnosis are key points for individualized treatment. Ultimately, gene expression profiles can be used to determine whether a patient needs a second-generation TKI.
How to treat chronic-phase CML
First, patients are evaluated diagnostically based on medical history, basic status, presence of comorbidities, and presence of cardiovascular risk factors. Laboratory tests include blood cell count, leukocyte classification, relevant metabolic indicators, LDH levels, and PCR testing for BCR/ABL1. If BCR/ABL1 is positive, a bone marrow aspiration and biopsy is performed to determine the stage of CML and to obtain a mid-secession cytogenetic sample. Subsequently, a Sokal score was calculated and an electrocardiogram was performed to determine the timing of the QT interval. Treatment was initiated with imatinib 400 mg/dose, QD, with an unrestricted diet and an extra glass of water daily. In case of adverse reactions, the drug is stopped for 4-5 days. During the first month of treatment, patients will be evaluated weekly for adverse reactions and blood counts will be checked. If blood counts are reduced, blood transfusions or filgrastim can be administered without discontinuing the drug. Hematologic parameters will be controlled in most patients after 1-2 months of treatment. For patients with high Sokal scores, initial use of dasatinib and nilotinib is recommended. These two drugs are more potent and have a relatively high probability of achieving EMR and MMR. However, it is also important to be aware of the adverse effects of both drugs. Dasatinib should not be used in patients with pulmonary disease or gastrointestinal bleeding, while nilotinib should be used with caution in patients with diabetes, liver disease or cardiovascular risk factors. Review the PCR after 3 months of treatment and if the patient obtains an EMR and can tolerate the prior TKI, continue treatment with that TKI and continue review after 3 months. If EMR is not achieved after 3 months of imatinib, it is recommended to discontinue imatinib and switch to a second-generation TKI. for patients whose hematologic parameters are not controlled after 3 months of treatment, bone marrow examination and testing for mutations in the ABL1 kinase gene will be performed. For patients who fail to achieve EMR with two or more TKI, allogeneic stem cell transplantation can be performed in the chronic phase.