CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Nurses: 1.00 Nursing contact hour
Released: March 01, 2022
Expiration: February 28, 2023
In 2001, imatinib became the first approved TKI for the treatment of CML. Imatinib and subsequently approved TKIs (bosutinib, dasatinib, nilotinib, ponatinib) and the STAMP inhibitor asciminib have profoundly changed the patient experience and clinical outcomes in CML. These targeted drugs have substantially improved the management of patients with CML and made optimistic goals more realistic.
It is clear that the natural history of the disease has been substantially changed by these targeted therapies. Today, many reports have shown that the life expectancy of a patient diagnosed with chronic-phase CML is very similar to that of the general population. This means that a patient with good access to individualized treatment, who is appropriately monitored and managed and who is adherent to therapy, will likely not die of CML and can have a normal life with normal activities.
However, many challenges remain. A multidisciplinary team approach with an engaged patient is critical, given that CML is a chronic disease with multiple decision points and the need for changes to occur quickly. Treatment must factor in the many targeted therapy choices, along with other challenges that may develop during the course of therapy, including resistance mutations, drug toxicity profiles, as well as adjusting dosing based on a patient’s characteristics and comorbidities. It is also important for HCPs to understand the key differences among the various therapeutic agents available and to know how to use them for maximum clinical benefit in different circumstances.
Achieving optimal outcomes requires balancing all these factors with the patient’s goals and the use of adequate monitoring. In the short term, it may not matter whether the strict guidelines are followed, but in the long term, differences emerge depending on whether the patient is monitored and managed appropriately, how physicians help the patient cope with and manage AEs, and the patient’s ability to remain adherent to their prescribed regimen. We use all of the tools that we have at our disposal, including consultations with other experts, such as cardiologists or endocrinologists, as the need arises. In the end, we need to make sure that the patient has the best possible outcome. Some patients may improve enough to consider the possibility of treatment discontinuation, whereas other patients may benefit more from switching to a different therapy due to intolerance or resistance (eg, disease progression). The intent of this activity is to help HCPs recognize all of these scenarios and manage them appropriately.
As of early 2022, 5 anti–BCR-ABL1 TKIs and 1 BCR-ABL1 STAMP inhibitor have been approved as treatment for CML.1-6 All first-generation and second-generation TKIs are approved for both frontline and second-line therapy (for imatinib, the second-line indication is after failure of interferon). The third-generation TKIs—ponatinib and STAMP inhibitor asciminib (approved in late 2021)—are characterized by their ability to inhibit the T315I mutation and are approved as second-line or later therapy for adult patients with CML in chronic phase with intolerance or resistance to ≥2 prior TKIs, or in adults with CML in chronic phase and the T315I mutation. All these targeted drugs are approved for accelerated-phase CML except for asciminib, and all are approved for blast-phase CML except for asciminib and nilotinib.
It is important to recognize that the dose varies for each of these drugs between the different phases of the disease and between different indications. For example, for asciminib, the dose for patients who are resistant or intolerant to previous TKIs and who do not have the T315I mutation is either 40 mg twice daily or 80 mg once daily. But for patients with T315I, the dose is 200 mg once daily. Of note, this drug must be given 2 hours after or 1 hour before any meal, for example, on an empty stomach.
With bosutinib, the frontline dose is 400 mg once daily, but the dose for second or subsequent lines of therapy is 500 mg once daily. This drug is given with food.
Dasatinib is given at 100 mg once daily in the chronic phase, but 140 mg once daily for the accelerated or blast phase. It can be given with or without food.
Imatinib is given at 400 mg once daily in the chronic phase, but 600 mg once daily in advanced stages. Imatinib is typically taken with food.
Nilotinib is given at 300 mg twice daily in the frontline setting, vs 400 mg twice daily in the resistant or intolerant second-line setting. Like asciminib, nilotinib is given on an empty stomach.
Ponatinib is given at 45 mg once daily for chronic, accelerated, or blast phase. However, once the patient achieves a response in the chronic phase, the dose can be dropped to 15 mg once daily to minimize AEs.
To optimize the management of patients with CML, it is important to keep in mind these differences in dosing and schedule, and whether these targeted agents are administered with or without food.
Clinical Considerations Primary Management of Chronic-Phase CML
Today, most patients with CML are diagnosed in the chronic phase. Many are asymptomatic and the presence of CML is identified incidentally, for example, in a routine blood check for an annual physical. Of importance, as good as outcomes are with current targeted therapies, if patients do not receive treatment or are not properly treated, eventually they will progress from an indolent chronic phase, with splenomegaly and leukocytosis, through the accelerated phase with aggressive features, and eventually to the blast phase.7
CML is characterized by the Philadelphia chromosome, which occurs when the ABL1 gene from chromosome 9 joins to the BCR gene on chromosome 22; the resulting BCR-ABL1 fusion gene is oncogenic. The BCR-ABL1 protein has increased autonomous kinase activity, resulting in the development of anti–BCR-ABL1 targeted therapy, initially imatinib, then followed by the second-generation and third-generation targeted agents previously discussed.
Although all of these drugs are fairly specific against ABL1 kinase, they also may inhibit other kinases such as c-Kit and the PTK receptor. In addition, some of them inhibit Src (dasatinib and bosutinib), while others may inhibit the EGFR receptor, particularly ponatinib.
As mentioned, today the life expectancy of a patient with chronic-phase CML with proper management is very close to that of the general population. The goal of CML treatment, therefore, should be to optimize management so that the patient has a normal life expectancy, will not die of CML, and has his or her psychological and social needs met as well as medical needs.
After patients are diagnosed with CML, they are typically stratified according to risk using one of the prognostic risk scores that have been developed over the years.7 The first with broad application was the Sokal score, which has remained valuable for parameters such as response to outcome after treatment-free remission. Later, the Hasford score was developed primarily with the intent to be more predictive of outcomes with interferon after it was introduced. Both of these scores assign patients a low, intermediate, or high risk score. The Sokal and Hasford prognostic scoring systems, as well as the European Treatment and Outcome Study (EUTOS) and EUTOS long-term survival (ELTS), are all based on similar clinical elements such as age, spleen size, and the percentage of basophils. These risk category scores have remained highly predictive of outcomes with targeted therapies for CML even though they were developed long before TKIs were introduced. For example, the high-risk Sokal patients have shorter overall survival (OS), as seen in the randomized IRIS study of imatinib vs interferon for frontline therapy.8 In later studies comparing second-generation TKIs to imatinib (ENESTnd, DASISION), risk-scoring systems have been predictive of the rate of major molecular response with nilotinib, dasatinib, and bosutinib, as well as decreased progression to the accelerated phase and blast phase.9 In some settings, they have even been predictive of deeper molecular responses, for example, with bosutinib in the BFORE trial.10
In addition to identifying clinical factors to guide treatment, there has been increasing interest in developing new biomarkers and molecular features that can better define risk. Recently, it has been reported that some patients at the time of CML diagnosis may have mutations in genes that are associated with other cancers (eg, ASXL, DNMT3, TET2) that may predict a worse outcome.11 These are not routinely tested for today, but they may be used in the near future.
This table shows the equations used to calculate the risk for an individual patient with chronic-phase CML. The Sokal and Hasford scoring systems were developed first, followed by the EUTOS scoring system, which attempted to simplify risk assessment using only basophils and spleen size, eliminating the intermediate score. The most recently developed scoring system is ELTS, which was developed to predict the risk of CML-related death, despite the fact that most patients with CML receiving targeted therapy die due to other causes. Nevertheless, the ELTS system is useful to predict the risk of dying of CML, for example, by progression to the blast phase.
All 4 scoring systems are predictive and remain in use. The Sokal system is the most widely used, although in Europe the ELTS is rapidly gaining momentum. Of note, online calculators are available here for each scoring system.
Now that multiple BCR-ABL1–targeted therapies are available, physicians may be challenged to select the optimal frontline treatment for an individual patient with CML; age, medical history, comorbidities, and toxicity profiles all play a role.12 The decision is further affected by the goals of the patient. One important aspect of the second-generation TKIs is a better probability of deeper molecular responses than imatinib; by contrast, imatinib has fewer high-risk AEs but a lower probability of deeper molecular responses.
Although all the TKIs are generally safe, they have unique toxicity profiles that can help physicians and patients tailor the choice of the best first-line treatment for each individual. For example, if a patient has risk features for developing pleural effusions (eg, lung disorders, uncontrolled hypertension) and is elderly, it may be prudent to avoid dasatinib, which is the TKI that has the highest risk of pleural effusion.3 Similarly, a patient with a history of, or risk factors for, pulmonary arterial hypertension should also avoid dasatinib, as it can cause this more frequently than any other TKI. Dasatinib is also not a preferred choice for patients at risk for hemorrhagic complications, as it has been associated with bleeding even in the absence of thrombocytopenia. Of course, all of the TKIs can cause thrombocytopenia and thereby an increased risk for bleeding, but with dasatinib this may occur due to treatment-related platelet dysfunction.
For patients who have uncontrolled diabetes, nilotinib should be used with caution because it raises glucose levels, which makes managing their diabetes more challenging.5
Those patients with significant risk factors for arterial occlusive events such as coronary artery disease, cerebrovascular events, or peripheral artery disease may not be candidates for ponatinib, which has a particularly high risk for these events.6 This risk can be minimized by using response-directed dose adjustments, but ponatinib should still be used with caution here. In the frontline setting, dasatinib and nilotinib both have a similar risk for arterial occlusive events, so it is better to avoid these drugs in patients at high risk and use either bosutinib or imatinib instead.
For patients with existing hepatic impairment, bosutinib is not the best choice as it is associated with the highest risk for liver dysfunction.2 Ponatinib also has liver toxicity concerns, but it is not used in the frontline setting.
Renal impairment, or at least a decrease in the glomerular filtration rate, is a risk with both imatinib and bosutinib. It is not clear that this represents kidney damage, but rather decreased reabsorption of creatinine. However, it may be prudent to avoid imatinib and bosutinib in patients with some renal dysfunction.
Patients who have a history of pancreatitis are at risk for treatment-related increases in lipase and amylase and, occasionally, clinical pancreatitis, and they should be closely monitored if receiving frontline therapy with nilotinib. This is particularly true with asciminib, which is used in later-line therapy.1
HCPs need to become familiar with the AEs of each TKI and identify each CML patient’s comorbidities or risk factors to minimize the risks inherent in treatment.
Studies of Frontline BCR-ABL TKIs in CML
The phase III IRIS study helped define TKIs as the frontline standard of care in newly diagnosed CML. In this study (N = 1106), patients with newly diagnosed CML in the chronic phase were randomized to receive either imatinib or the standard of care at that time, interferon plus cytarabine.13 Results showed a significantly higher probability of major cytogenetic response (MCyR), which was a primary endpoint in trials around 20 years ago. Although no survival benefit was evident initially, long-term follow-up at 10 years shows a modest but statistically significant survival benefit: 83.3% for imatinib vs 78.8% for interferon. This is remarkable given that the majority of patients on interferon crossed over to the imatinib arm, and most did so very early.
Following IRIS, a series of studies were conducted to compare second-generation TKIs to imatinib. In the phase III ENESTnd trial, 846 patients with newly diagnosed, Ph-positive, chronic-phase CML were randomized to nilotinib at either 300 mg or 400 mg twice daily vs imatinib 400 mg once daily.14 The results established nilotinib 300 mg twice daily as a standard of care for frontline therapy, with 400 mg reserved for the salvage setting.
As shown here, at 10 years the incidence of major molecular response (MMR) was significantly higher for patients who received either dose of nilotinib compared with imatinib (~79% vs 63%, respectively). Likewise, the incidence of deeper molecular responses, MR4.5, at 10 years was 61% with nilotinib compared with 39% with imatinib.
MMR and MR4.5 were also evaluated in the phase III DASISION study of dasatinib vs imatinib in patients with previously untreated CML (N = 519).15 At 5 years of follow-up, both MMR and MR4.5 (molecular responses with a 4.5-log reduction in BCR-ABL1 transcript from baseline) were significantly superior with dasatinib, with good separation between the curves. The cumulative rate of MMR was 76% with dasatinib vs 64% with imatinib (P = .0022). At 5 years, MR4.5 was also superior with dasatinib, at 42% vs 33% for imatinib (P = .0251). Clearly, dasatinib has not only superior benefit vs imatinib, but a longer duration of benefit as well.
Importantly, as seen in both ENESTnd and DASISION, not every patient will achieve an MMR, and certainly not MR4.5, but that is not necessarily cause to change therapy.
BFORE was a randomized, phase III trial comparing bosutinib 400 mg once daily to imatinib in 536 patients with newly diagnosed chronic-phase CML.10
In the 12-month analysis of that study, rates of complete cytogenetic response (CCyR) were 77% with bosutinib vs 66% with imatinib, a significant difference (P = .0075). Of note, those differences have been sustained for up to 5 years of treatment, which is the longest follow-up for the BFORE study available to date.16
As shown here, at 5 years, the comparison to imatinib was similar to the studies comparing nilotinib and dasatinib with imatinib: The results showed an early benefit of bosutinib in MMR rates and in the deeper molecular responses (MR4 and MR4.5).
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