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
AEs associated with BCR-ABL1 inhibitors in CML tend to be infrequent, mild, and tolerable, and easily managed. Most patients experience early, mild to moderate AEs that can be easily controlled or which spontaneously resolve. Although these drugs are generally safe, all of them carry some risk for developing certain adverse events. HCPs’ ability to properly manage these AEs helps provide the best outcomes to patients, including better quality of life. Also, HCPs should seek to minimize changing therapy, which is sometimes done too frequently. Managing AEs is highly preferable to immediately changing therapy due to AEs.
This diagram shows some of the most important AEs for each of the BCR-ABL1 inhibitors currently approved in CML.1-6 All of these drugs are associated with myelosuppression (neutropenia, thrombocytopenia, anemia) and, to some extent, liver dysfunction (electrolyte abnormalities, hyperphosphatemia).
Certain events may be more frequent with one drug more than others. For example, peripheral fluid retention is more common with imatinib, whereas other drugs have a more central fluid retention. More myalgias and muscle cramps are seen with imatinib, as well as hypophosphatemia and gastrointestinal AEs (diarrhea, nausea).
With nilotinib, the elevation of pancreatic enzymes (amylase, lipase) is common, but fortunately true clinical pancreatitis is rare. These enzyme elevations need to be monitored closely. Nilotinib also can cause the elevation of bilirubin, mostly in patients with Gilbert’s syndrome, as well as QT prolongation, which is a black box warning in the label.
The main AEs to be aware of with dasatinib are pleural and pericardial effusion and occasionally ascites. The mechanism is not clearly understood, but this can require discontinuation of dasatinib. As mentioned previously, dasatinib is also associated with a bleeding risk independent of platelet count, possibly related to platelet dysfunction.
Bosutinib is most frequently associated with diarrhea, but fortunately this is usually manageable. Bosutinib also can cause rash, as well as elevated transaminases.
With ponatinib, hypertension is common. This third-generation TKI also inhibits the VEGF receptor, which can lead to hypertension, as well as arterial occlusive events. This is a class effect seen with most of the TKIs, but ponatinib may have the highest risk. Ponatinib is also associated with the elevation of liver function tests and the elevation of pancreatic enzymes.
With asciminib, the most notable AE is the elevation of lipase and amylase.
It is important for HCPs to keep the potential for each of these AEs in mind when selecting a BCR-ABL1 inhibitor for a patient with CML.
Hughes and colleagues conducted a phase I dose-escalation study of asciminib in 141 patients with chronic-phase CML and 9 with acute-phase CML who had failed at least 2 lines of prior treatment.36 The toxicity profile for asciminib shows that the most common events were fatigue (29%), headache (28%), lipase elevation (27%), and arthralgia (24%), as well as nausea and diarrhea in approximately one quarter of patients. Grade 3/4 AEs were far less common, with the exception of lipase elevation in 10% of patients. Most of the time this is not associated with clinical pancreatitis, but it is important to monitor. HCPs should also be aware of the potential for hypertension, which was grade 3/4 in 9%, even though asciminib is not a VEGF receptor inhibitor.
It is important to monitor patients throughout the course of therapy to promptly address events such as this and to minimize the risk of more serious AE such as arterial occlusive events. The incidence of arterial occlusive events with asciminib is low, but it is important to monitor. Grade 3/4 myelosuppression was seen as well, with thrombocytopenia being the most common (9.3%), along with neutropenia and anemia (7.3% each).
Myelosuppression is particularly important to manage in patients receiving asciminib.1 For patients who develop grade 3 neutropenia (ANC <1.0 x 109/L) or grade 3 thrombocytopenia (platelets <50 x 109/L), it is important to stop therapy and then monitor weekly. If the patient recovers within 2 weeks, resume at the same starting dose. If the patient takes more than 2 weeks to recover, reduce the dose by 1 dose level. If they have a recurrence, further dose adjustments are possible but may be protracted. These AEs typically resolve after 1 transient interruption, sometimes after dose reduction, and improve over time as the patient responds to therapy.
Patients receiving asciminib must be monitored for lipase elevation; if it is more than 2 times the upper limit of normal (ULN), stop therapy, monitor, and then resume treatment when lipase drops to below 1.5 times the ULN. The dose at this point needs to be reduced to minimize the risk of recurrence. If the event is recurrent, treatment may need to be discontinued and other options considered. If the AE does not resolve at all, discontinue therapy. It is also important to investigate other causes of pancreatitis, because there can be other reasons that are critical to correct.
For most other grade ≥3 AEs, hold therapy until it resolves to grade ≤1 and then resume therapy, usually with a reduced dose. Permanent discontinuation may be needed if not resolved.
Diarrhea is the most common AE of bosutinib, seen in 70% of patients.2 However, it’s largely grade 1/2. Less than 10% is grade 3/4, and patients rarely need to discontinue therapy because of diarrhea. Other AEs associated with bosutinib include myelosuppression, with thrombocytopenia seen in 35% of patients (14% grade 3/4) and anemia in 19%. However, there is less neutropenia compared with imatinib, perhaps because it doesn’t inhibit c-Kit. Other grade ≥3 AEs include the elevation of liver function tests (10% to 20%). Rash is seen in approximately one third of patients but is mostly grade 1/2 and can be managed with supportive care.
Myelosuppression management is similar for all the BCR-ABL inhibitors. For bosutinib, if patients develop grade 3 neutropenia (ANC <1.0 x 109/L) or grade 3 thrombocytopenia (platelets <50 x 109/L), stop therapy and then monitor weekly.2 If the patient recovers within 2 weeks, resume at the same starting dose. If the patient takes more than 2 weeks to recover, reduce the dose by 100 mg. Additional reductions can be used if there is further recurrence. Growth factors can be beneficial, particularly if a patient has persistent neutropenia. Eltrombopag has been used to manage recurrent thrombocytopenia with TKIs in clinical trials, but this is not an approved indication and is not available for routine standard of care.
Anemia is a risk with bosutinib but can be caused by or exacerbated by other factors, including deficiencies of iron, vitamin B12, and folates. Some symptomatic patients may need transfusion support.
Liver toxicity is a key concern with bosutinib, and patients must have liver function tests throughout the course of therapy. If liver transaminases (alanine aminotransferase ALT or aspartate aminotransferase AST) increase to more than 5 times the ULN, stop therapy until it resolves to less than 2.5 times the ULN (eg, grade 1), then reduce the dose once therapy is resumed. However, if liver transaminase levels take more than 4 weeks to recover, or if there are several recurrences, treatment should be permanently discontinued. Hy’s law is an observation that drug-induced hepatocellular injury in the absence of a significant obstructive component will lead to death or transplantation in 10% to 50% of cases.37
If Hy’s law is met, the patient should discontinue bosutinib treatment to avoid further risk of liver damage.
As mentioned earlier, diarrhea tends to be manageable and transient, resolving in the first few weeks of therapy. However, if a patient is experiencing grade 3/4 diarrhea, it is better to hold bosutinib, manage aggressively, and always investigate other causes. Once the diarrhea has resolved to grade 1, therapy can be resumed at a lower dose of 400 mg once daily.
Most other AEs from bosutinib can also be managed with holding therapy and then resuming at a reduced dose.
Dasatinib is most commonly associated with fluid retention such as pericardial effusion, pleural effusion, and, occasionally, ascites.3 Pleural effusion can happen in 25% to 30% of patients. Pericardial effusion is not as common, and most of the time it’s grade 1/2 and manageable, but occasionally it’s grade 3/4 (3%/1%) and can be recurrent. Headache is commonly seen with dasatinib (33%), more than with other TKIs. Other risks include diarrhea, fatigue, dyspnea, and musculoskeletal pain in approximately 25% of patients each.
Once again, grade 3/4 myelosuppression is a concern, including neutropenia in 36% of patients, thrombocytopenia in 24%, and anemia in 13%.
Additional concerns with dasatinib, as mentioned earlier, include hemorrhage and cytopenias.3 Pulmonary artery hypertension is a concern but rare and reversible. If it develops, dasatinib should be permanently discontinued, just to not take any chances; the implications of pulmonary hypertension are significant and it could be persistent.
Mild pleural effusion can be treated by holding therapy, managing the AEs, and then resuming therapy with a lower dose. Quite often this can be found only by great clinical suspicion because the symptoms may not be very specific (eg, cough, shortness of breath, and occasionally pleuritic chest pain). HCPs must remain alert to these signs and obtain a chest x-ray as needed. More severe pleural effusion may require measures like thoracentesis and supplemental oxygen. Often the fluid can be drained, but if the patient requires thoracentesis more than once, switching to a different BCR-ABL1 inhibitor is warranted.
For most other grade 3/4 AEs, it is appropriate to hold dasatinib until resolved, then resume at a reduced dose.
Imatinib is associated with more AEs than the other TKIs, but also with the least serious AEs; very few are grade 3/4.4 Fluid retention (eg, peripheral edema, lower extremities, periorbital edema) is seen in 62%, but only grade 3/4 in 2.5%. Muscle cramps are much more common with imatinib (~50%; 2.2% grade 3/4) than with the other TKIs, as is musculoskeletal pain. All of these AEs can be managed and are transient.
Of note, there is no clear evidence that imatinib increases the risk of arterial occlusive events, and it is considered to be neutral in this regard; the other TKIs all increase this risk to varying degrees.
As see in this table, managing the myelosuppression associated with imatinib is similar to how it is managed with other TKIs.4
Liver toxicity is a concern with imatinib, and treatment should be held if the bilirubin increases to more than 3 times the ULN or transaminases to more than 5 times the ULN (eg, grade 3 AEs). Once these resolve, you can resume imatinib at a reduced dose. If the liver toxicity is severe, changing therapy should be considered.
Muscle cramps can be managed conservatively with electrolyte replacements (eg, quinine) and can resolve well.
The most common AE associated with nilotinib is rash, which affects nearly 40% of patients with chronic-phase CML but is grade 3/4 in less than 1%.5 Nilotinib does cause some gastrointestinal toxicity, but it is uncommon and typically grade 1/2 (19%). In fact, most AEs from nilotinib are grade 1/2, as seen in this table. The most common grade 3/4 AEs are myelosuppression: neutropenia (12%), thrombocytopenia (10%), and anemia (4%).
Nilotinib-related QT prolongation is uncommon but it can have significant implications.5 Physicians should perform an EKG at baseline and again either a week later or whenever a change in dose of nilotinib or a new addition of concomitant medications is implemented. If the QT prolongation is grade 3 (eg, >480 msec), stop nilotinib. In addition, ensure that the patient’s potassium and magnesium are at normal levels to decrease the risk of further increases in the QTc prolongation; sometimes that is the sole reason for the prolongation. Once the QTc resolves, resume therapy, potentially with a nilotinib dose reduction.
Managing myelosuppression with nilotinib is similar to how it is managed with the other TKIs discussed: Hold until the AE is resolved, then resume at the same or a lower dose. Patients with severe anemia may require transfusion support.
Regarding liver and pancreatic enzyme elevations, if it is a grade 3 elevation, hold nilotinib until the levels resolve to grade 1 and then resume therapy with a reduced dose.
Peripheral arterial occlusive disease would require the permanent discontinuation of nilotinib.
AEs associated with ponatinib include a high rate of hypertension (69%), with 42% of grade ≥3, which requires very close monitoring and aggressive management.6 With proper management, most patients can continue therapy with ponatinib.
Rash is also frequently seen (63%) but is only rarely grade ≥3 (3%). Skin issues from ponatinib can also include very dry skin or psoriasis-like plaques.
Regarding gastrointestinal toxicity, constipation is a particular concern, affecting more than 40% of patients, but again with a low rate of grade ≥3 (3%). Of note, like other TKIs, ponatinib carries risks of arterial occlusive events and myelosuppression.
Grade 3/4 hematologic abnormalities have been seen as well, including neutropenia in 23%, thrombocytopenia in 35%, and anemia in 8%.
Management of the myelosuppression associated with ponatinib is similar to that of the other TKIs, based on holding treatment until the AE resolves, and resuming at lower doses, as seen in the table.
Likewise, ponatinib-associated liver toxicity is managed similar to the other TKIs: Hold, wait for resolution to grade 1, and then resume therapy at a lower dose. Discontinue if it does not resolve or recurs, or if it meets Hy’s law (discussed earlier).
For pancreatitis, it is common to see the elevation of lipase and amylase in the absence of clinical pancreatitis. In this situation, hold ponatinib and once it resolves, resume with a lower dose, or discontinue as needed.
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