CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 15, 2024
Expiration: February 14, 2025
Case 3: A Patient With Intolerance to Initial Therapy
Now, let’s consider a 51-year-old man with hypertension who was diagnosed with chronic-phase CML and was started on bosutinib at the approved dose of 400 mg daily. He is presenting to clinic for evaluation of ongoing diarrhea. His laboratory values revealed mild transaminitis with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) of 62 U/L and 71 U/L, respectively. For this patient, my recommendation is to reduce the dose of bosutinib. It can be reduced to 200 mg daily along with symptomatic treatment of the diarrhea and monitoring of liver function tests (LFTs). Once symptoms improve, the dose can be increased to 300 mg daily.
Stepwise dosing of bosutinib has been shown to be associated with a lower risk of AEs while maintaining efficacy.23 It is preferred that patients start treatment at 100 mg daily with dose increases every 2 weeks by 100 mg to minimize the risk of side effects while reaching for the target dose.
Following the dose reduction, the patient’s diarrhea improved and his LFTs normalized. His dose was increased to 300 mg daily, and he remained on that dose. His 3-month, 6-month, and 12-month BCR::ABL1 transcript levels were 5%, 0.8%, and 0.12%, respectively. He has remained on bosutinib 300 mg daily for 14 months to date, and is tolerating it well. For this patient, and others, it is key to emphasize during follow-up appointments that adherence to TKI therapy is very important for the success of CML treatment.
Toxicity Spectrum of BCR::ABL1 Inhibitors in Adults
In addition to careful monitoring for treatment response, optimal outcomes also depend on patient adherence.24 Reasons for suboptimal adherence to therapy can be multifactorial but optimal communication with providers about AEs is essential. AEs that result in a negative effect on quality of life will likely result in decreased adherence. Providers can foster an environment where patients feel comfortable discussing their concerns, side effects, and any challenges they face in adhering to their medication.
Most patients experience early, mild to moderate AEs that can be easily controlled or that spontaneously resolve. Although these drugs are generally safe, all of them carry some risk for developing certain AEs. HCPs’ ability to properly recognize and manage these AEs helps provide the best outcomes to patients, including better quality of life.
This diagram shows some of the most important AEs for each of the BCR-ABL1 inhibitors currently approved in CML.3-8 All of these drugs could cause myelosuppression (neutropenia, thrombocytopenia, anemia) and, to some extent, elevated transaminases and electrolyte abnormalities.
Certain events may be more frequent with one drug compared with the 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 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. 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 elevation of LFTs and pancreatic enzymes.
With asciminib, the most notable AEs are elevation of lipase and amylase and hypertension.
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. Next, we will review common AEs and management of key AEs with each agent.
Selected Clinically Relevant AEs With TKIs and STAMP Inhibitor in CML
Myelosuppression is particularly important to manage in patients receiving therapies for treatment of CML. Specific recommendations for managing myelosuppression are in the prescribing information for each agent.
Diarrhea is the most common AE of bosutinib, seen in 75% of patients with newly diagnosed CML.4 However, it is largely grade 1/2, with less than 10% being grade 3/4, and patients rarely need to discontinue therapy because of diarrhea. Other AEs associated with bosutinib include abdominal pain, fatigue, and respiratory tract infection. Other grade ≥3 AEs include hepatic dysfunction (27%) which may be elevations in ALT, AST, alkaline phosphatase, and/or total bilirubin. Rash is seen in approximately 40% of patients but is mostly grade 1/2 and can be managed with supportive care.
Dasatinib is most commonly associated with fluid retention such as pericardial effusion, pleural effusion, and, occasionally, ascites.5 Pleural effusion can happen in 25% to 30% of patients. Pericardial effusion is not as common, and most of the time it is grade 1/2 and manageable, but occasionally it is grade 3/4 (3%/1%) and can be recurrent. Using dasatinib at the reduced dose of 50 mg daily in newly diagnosed chronic-phase CML was shown to decrease the incidence of AEs while maintaining efficacy compared to the approved dose of 100 mg daily.10
Imatinib is associated with more AEs than the other TKIs, but also with the least serious AEs; very few are grade 3/4.3 Fluid retention (eg, peripheral edema, lower extremities, periorbital edema) is seen in 61%, but is only grade 3/4 in 2.5%. Muscle cramps are much more common with imatinib than the other TKIs, as is musculoskeletal pain. All of these AEs can be managed and are transient. 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.
The most common AE associated with nilotinib is rash, which affects 40% of patients with chronic-phase CML but is grade 3/4 in 2%.6 Nilotinib does cause some gastrointestinal toxicity (in 19% of patients), but it is uncommon and typically grade 1/2. Nilotinib has been noted to be associated with impaired glycemic control so patients should be monitored for worsening diabetes.2
AEs associated with ponatinib include a high rate of hypertension (42%), with 30% of grade ≥3, which requires very close monitoring and management.7 With proper management, most patients can continue therapy with ponatinib. Rash is also frequently seen (75%) but is only rarely grade ≥3 (9%). Skin issues from ponatinib can also include very dry skin or psoriasis-like plaques. Regarding gastrointestinal toxicity, constipation is a particular concern with ponatinib, but with a low rate of grade ≥3 events. Of note, like other TKIs, ponatinib carries risks of arterial occlusive events and myelosuppression.
The toxicity profile for asciminib shows that the most common events were upper respiratory tract infections (26%), musculoskeletal pain (24%), and headache (21%).8 Grade 3/4 AEs were less common, with the exception of lipase elevation in 4.5% 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 7%, even though asciminib is not a VEGF receptor inhibitor.
Management of Treatment Intolerance
In cases of treatment intolerance, reducing the dose should be the first step before changing therapy.25 If a patient is intolerant to frontline imatinib, a second-generation TKI like dasatinib (20 mg to 50 mg daily) or another lower-dose second-generation TKI is recommended. For those intolerant to frontline second-generation TKIs, switching to another second-generation TKI with a different safety profile is advised, considering the patient's comorbidities. Imatinib can be a second-line option for patients stopping second-generation TKIs due to toxicity (not resistance). In the rare event of intolerance to imatinib and all 3 second-generation TKIs, lower doses of ponatinib (15 mg daily) or asciminib (lower doses not yet studied) may be considered.
Management of Prohibitive Toxicities
In case of prohibitive toxicities, the TKI should be discontinued and the treatment should be changed to an alternative TKI.25 These toxicities include: 1) recurrent pleural effusions (mainly with dasatinib); 2) pulmonary hypertension (typically with dasatinib); 3) arterio-occlusive or vaso-occlusive events (more common with nilotinib and ponatinib); 4) pancreatitis (mostly with nilotinib and ponatinib); 5) severe hypertension with ponatinib that doesn't respond to antihypertensive treatments; 6) enterocolitis with bosutinib; 7) neurotoxicity (rarely with imatinib and dasatinib); and 8) immune-mediated AEs such as pneumonitis, hepatitis, myocarditis, or nephritis.
Trials With TKI Dose Reduction or Intermittent Dosing
Several groups have explored potential intermittent or dose de-escalation strategies. Dose modifications have the potential to improve adherence and reduce treatment interruptions due to AEs.
The phase II study on intermittent dosing of imatinib in CML (INTERIM) evaluated 76 patients aged 65 years or older who were stable on imatinib for 2 or more years.19,26 Imatinib was given on a 1-month-on and 1-month-off schedule. After 6 years of follow-up, 21% lost MMR and CCyR, and regained MMR and CCyR following resuming a continuous schedule.
De-escalation and discontinuation of TKI therapy was evaluated in the DESTINY phase II study.27 Adult patients (n= 174) with chronic-phase CML were stable on imatinib, nilotinib, or dasatinib for 3 or more years.27 Treatment doses were decreased to half the standard dose for 1 year, followed by discontinuation for 2 years. Patients were stratified into MMR and MR4 groups. After 3 years, recurrence-free survival rates were 35% and 72% in the MMR and MR4 groups, respectively. Upon resumption of treatment, anyone with a recurrence regained MMR.
The intermittent schedule strategy used in the INTERIM study described above was used as the control arm in the ongoing OPTkIMA phase III trial.28 Adult patients (n = 215) with chronic-phase CML stable on imatinib, nilotinib, or dasatinib for 2 or more years were randomized to receive either intermittent dosing of TKI (control arm) or to the experimental arm which was the same intermittent schedule for Year 1, followed by 1 month on TKI and 2 months off for Year 2, and 1 month on TKI and 3 months off for Year 3. After 1 year of patients receiving the 1-month-on, 1-month-off (like the INTERIM study schedule), results were consistent with those of the INTERIM study, with 81% maintaining MMR. At the final follow-up, MMR loss was lower in the control arm compared to the experimental arm (27% vs 46%, P = .005) The higher rate of MMR loss in the experimental arm did not result in further disease progression.
Intermittent dosing remains an investigational strategy that should only be done in the context of a clinical trial at this time.
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