Posted: Wednesday, September 11, 2019
Ponatinib: A Third-Generation Tyrosine Kinase Inhibitor
Treatment of chronic myeloid leukemia (CML) was revolutionized in the early 2000s with the approval of imatinib, a first-generation oral tyrosine kinase inhibitor (TKI).1 Subsequent development of the second-generation TKIs—dasatinib, nilotinib, and bosutinib—has expanded the therapeutic options and clinical quandaries faced by hematologists who treat patients with CML.2 Most hematology clinicians are familiar with both the expected efficacy and drug-related adverse effects of these oral treatments. Unfortunately, as with cancer therapy for most malignancies, resistance develops eventually; in CML, 20% of those cases are associated with the emergence of the T315I mutation.3
Oral ponatinib is a third-generation TKI designed to inhibit native BCR-ABL1 tyrosine kinase and several BCR-ABL1 mutants, including T315I.4 The onset of the T315I mutation (found in up to 20% of resistant patients with CML) confers resistance to all available first- and second-generation TKIs (imatinib, nilotinib, dasatinib, and bosutinib).3 Ponatinib is about 500 times more potent than imatinib5 and has been shown to overcome T315I-associated resistance.3,5 However, this enhanced activity comes at a cost: ponatinib is substantially more toxic, in terms of serious safety issues, than earlier TKIs.
According to Jessie R. Signorelli, PharmD, BCOP, Clinical Leukemia Pharmacist at the Massachusetts General Hospital in Boston, “Ponatinib is utilized in patients for whom the other TKIs are either not efficacious or not tolerated. In addition, ponatinib is utilized earlier on if a T315I mutation is identified.” She observed that due to its safety profile, ponatinib is viewed by many practitioners as “last-line” treatment. Sometimes patients on a first- or second generation TKI will not achieve response goals, defined by the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Myeloid Leukemia as BCR-ABL1 IS ≤ 10% at 3 and 6 months or BCR-ABL1 IS ≤ 1% at 12 months.6
“Before jumping to conclusions,” Dr. Signorelli cautioned, “we try to determine whether the patient has been adherent. If the drug has not been taken consistently, that could explain why the BCR-ABL1 hasn’t decreased as much as expected. Likewise, we need to check into drug interactions7 to determine whether other medications may be interfering with the activity of the TKI.” Once those types of reasons are ruled out, she continued, a resistance panel (ie, mutation analysis) is ordered. “If a T315I mutation is reported, ponatinib is considered earlier in the treatment sequence. In general, though, patients are treated on a case-by-case basis, and ponatinib is not considered until a second-generation TKI has been considered.”
Javier Pinilla-Ibarz, MD, senior member in the Department of Malignant Hematology at the Moffitt Cancer Center and Research Institute in Tampa, Florida, has had extensive clinical experience with ponatinib. “I consider ponatinib in situations where there has been failure after a second-generation TKI,” he told JNCCN 360. He noted that few patients do not respond adequately to first- or second-generation agents. “However, when it happens,” he said, “I don’t think it is necessary to try all of the second-generation options—and fail—before using ponatinib. If there has been true failure on imatinib AND true failure on one second-generation drug, such as dasatinib, nilotinib, or bosutinib, in experienced hands, ponatinib may be a viable option.”2
True Resistance or Poor Adherence?
Evaluating adherence can sometimes be challenging, Dr. Signorelli remarked. “One option is to call the patient’s pharmacy to see whether the timing of refills is roughly accurate. If only a 30-day supply was dispensed in 60 days, it’s likely the patient is not taking the medication once daily, as prescribed,” she explained.
Simply interviewing the patient can also be revealing. “Questions such as, ‘How do you remember to take your medication every day?’ or ‘What are some things you do to remind yourself to take your medicine?’ can lead naturally to a conversation about adherence and even to practical suggestions,” Dr. Signorelli continued. If a particular drug needs to be taken on an empty stomach or at night, asking questions specifically tailored to those instructions can also reveal where the challenges might be.
Although patients with cancer are usually motivated to take their medication, Dr. Signorelli acknowledged that side effects such as overwhelming fatigue, muscle aches, or nausea might also make them reluctant to do so. It can be helpful to reassure patients, saying “I know it’s difficult right now and that you feel wiped out and achy, but these side effects have been shown to decrease over time.” Likewise, she pointed out that offering supportive care with antiemetics, antimotility agents, nonsteroidal anti-inflammatory drugs, or acetaminophen is critical to success with these TKIs. Patients may also be encouraged to try physical therapy and maintain an active lifestyle. This is especially important, she said, for those experiencing fatigue and musculoskeletal complaints.
Emergence of the T315I Mutation
Although emergence of the T315I mutation after initial treatment for CML diminishes response to first- and second-generation TKIs, Dr. Pinilla-Ibarz observed that the mutation “does not confer a proliferative advantage in the cancer cells of chronic phase CML. In fact, the resistant clone, due to T315I mutation, grows slowly. In the ‘old days,’ he recalled, “before the availability of ponatinib, when response to imatinib treatment for chronic phase CML started to slow because of the selection of the T315I mutation, we used to stop treatment to allow the disease to naturally overcome the slower-growing mutated clones. Then, when the T315I clones were overcome, we could reinitiate imatinib, and the process would start again. We couldn’t keep going indefinitely with that strategy, but we could buy some time in this way.” Dr. Pinilla-Ibarz emphasized that this approach could not be used in accelerated, blast phase CML or Philadelphia chromosome–positive acute lymphocytic leukemia, “but this is what we have observed in chronic phase CML.”
Treatment with ponatinib is associated with a variety of serious toxicities. Based on data from the PACE trial, arterial occlusive events (AOEs), such as myocardial infarction and stroke, and venous thromboembolic events (VTE), such as severe peripheral vascular disease, occurred in 31% (serious AOEs, 26%) and 6% (serious VTE, 5%) of patients with chronic phase CML, respectively.8 Even patients without cardiovascular risk factors at baseline, including individuals younger than 50 years of age, experienced these sequelae. Additionally, ponatinib-related heart failure and hepatotoxicity have occurred, and in some cases have resulted in death.
Whenever possible, Dr. Signorelli said, cardiovascular risk factors for atherosclerosis—diabetes, hypertension, hyperlipidemia, smoking, and estrogen use—should be controlled before ponatinib is started. Likewise, liver enzymes should be determined at baseline and then monitored at least monthly, she added. However, if hepatic impairment is noted at baseline or if the patient has a history of alcoholism, for instance, hepatic monitoring should be more frequent. Likewise, lipase levels should be closely monitored in a patient with a history of pancreatitis.
Coordinating With Cardiology Colleagues
“We coordinate with our cardiology colleagues to proactively reduce risk factors as much as possible before and during ponatinib treatment,” Dr. Pinilla-Ibarz said. “Aspirin and/or angiotensin-converting enzyme (ACE) inhibitors may be used, for example, to minimize risk. Hypertension, for example, is extremely common with ponatinib,” he pointed out. Our approach, which includes aggressive prophylaxis using aspirin and low-dose ACE inhibitors, undoubtedly may have contributed to the significantly lower incidence of cardiovascular events with ponatinib at our institution compared with those reported in the standard trials, Dr. Pinilla-Ibarz said.
We coordinate with our cardiology colleagues to proactively reduce risk factors as much as possible before and during ponatinib treatment.
Customizing the Starting Dose
The recommended starting dose of ponatinib is 45 mg once daily.9 Nevertheless, in phase II trials, 68% of patients required dose reductions to 30 mg or even 15 mg daily.8 “For those patients who are older, have hepatic or cardiovascular risk factors, or perhaps have heart failure or pancreatitis,” Dr. Signorelli cautioned, “it is prudent to consider starting at 30 mg (or even 15 mg to assess initial tolerability) rather than not to treat at all. Ideally, we would like to get risk factors such as diabetes and hypertension under control before starting ponatinib.”
A post hoc analysis of the PACE trial provided support for the efficacy and safety of reduced doses of ponatinib,8 and ongoing research is also evaluating responses at lower doses. Additionally, multivariate analysis has shown an association between dose intensity and adverse events.10 Unfortunately, the researchers also noted a time delay, which could be as long as 6 months, between a reduced dose and a reduction in adverse events. Therefore, it is often wise to start at a lower dose and to gauge tolerability and response carefully.
The critical milestone in treatment of chronic phase CML is assessment of key markers, such as BCR-ABL1 and cytogenetics, at the 3-month point, Dr. Pinilla-Ibarz explained. “Ponatinib generally exerts its activity quite rapidly, and most patients will demonstrate a response quickly. If there is no or minimal response to 30 mg of ponatinib at 3 months, we usually consider whether treatment should be discontinued. Generally, we do not increase the dose in that scenario,” Dr. Pinilla-Ibarz told JNCCN 360. However, “if a patient with a T315I mutation has been started on 30 mg of ponatinib and responds, but then requires a dose reduction to 15 mg, he or she may have a relapse in a few months. In such a scenario, we may be able to rescue that patient by increasing the dose. In other words, the IC50 for a patient with a T315I mutation may be borderline when using 15 mg of ponatinib, whereas 30 mg of ponatinib can maintain efficacy,” he said.
Dr. Pinilla-Ibarz generally starts patients with chronic phase CML on 30 mg of ponatinib, “although those with significant cardiovascular risk factors may be started at 15 mg.” Nevertheless, he stressed, these dosage decisions are highly individualized. “I might consider using 45 mg in someone with advanced, accelerated, blast phase disease, even if he or she is 80 years old,” he explained. There are some older adults with serious hematologic disease who have few comorbidities and may benefit from treatment that will prevent progression to a lethal leukemia. “Because we rarely if ever use 45 mg of ponatinib in our patients with chronic CML, the incidence of serious cardiovascular effects is lower than that described in clinical trials,” Dr. Pinilla-Ibarz said.
Dr. Pinilla-Ibarz observed that patients may not know that a symptom is drug-related, or “they may believe that it is ‘not bad enough’ to bother the medical team about. But, if we are aware, we can intervene early with loperamide, for example, if a patient has diarrhea. Likewise, if a patient becomes nauseous from treatment, I will call a prescription for an antiemetic into the pharmacy,” Dr. Pinilla-Ibarz said. “If the patient reports simple edema, we can use furosemide, checking weight and potassium levels frequently. Even the muscle cramps may be improved with Coenzyme Q10 or calcium supplements.”
Other Adverse Effects
Side effects associated with TKIs, such as ponatinib, include fatigue, muscle pain and muscle spasms, skin rash, and gastrointestinal effects, such as constipation or diarrhea. Because almost half of patients who are treated with these agents report some type of abdominal “pain,” the team might specifically talk about the potential for upset stomach, diarrhea, and nausea and what to do about it. Providing treatment options for relief of symptoms, with subsequently improved quality of life, may motivate patients to continue to take their medication. Taking the medication with food, for instance, may reduce or eliminate nausea, Dr. Signorelli suggested. Additionally, patients may be instructed to be alert for signs of jaundice, such as yellowing of the skin or the whites of the eyes or musty-smelling urine.
Too often, patients are quickly switched to another TKI. As a result, they burn through all of their options quickly.
Tolerance of the adverse effects associated with TKIs depends on the patient. Those who have been moderately intolerant with the other TKIs will not necessarily do better or worse with ponatinib, Dr. Pinilla-Ibarz observed. “Certainly, because of other considerations, we tend to start with lower doses of ponatinib, which may be easier to tolerate,” he said. However, there are no clinical trials to suggest that the side-effect profile of ponatinib is any different from other drugs in this class of TKIs.
Efforts should be made to offer supportive care that will help patients stay on their regimen. “Although we all acknowledge that some patients cannot tolerate TKIs, we should at least try to help them stick with therapy by managing their symptoms,” Dr. Pinilla-Ibarz counseled. “Too often, patients are quickly switched to another TKI. As a result, they burn through all of their options quickly.”
Rash and gastrointestinal side effects sometimes improve over time during treatment with ponatinib. Bone/joint pain and muscle discomfort, however, “do not appear to get better with time; some patients experience these effects whereas others do not,” Dr. Pinilla-Ibarz noted. Ibuprofen or acetaminophen might be used occasionally, he added, but if dose reduction does not improve bone and joint pain, and it is debilitating, the TKI may have to be discontinued. Abdominal pain is commonly reported with ponatinib and is often the reason that the dose is reduced. “Abdominal pain is more frequent and more intense with 45 mg of ponatinib than with 30 mg,” Dr. Pinilla-Ibarz asserted, also noting that the pain may be associated with lipase or amylase elevation or pancreatitis. Patients describe “crampiness,” which some investigators have attributed to vasospasms in the splenic circulation.
When patients first start on ponatinib, as with other TKIs, “I ask them to come to clinic weekly for monitoring. After the first month, if everything is going smoothly, they can come every 2 weeks. Thereafter, they can come monthly, and finally, every 3 months,” Dr. Pinilla-Ibarz explained. In contrast, “if amylase or lipase is elevated, platelets are low, or there are other signals that we need to monitor more carefully, we will continue to see the patient frequently.”
Where Do We Go From Here?
The most challenging aspect of using ponatinib for practitioners revolves around what to do next for these patients.
Despite the toxicity profile associated with ponatinib, by the time patients are considering last-line treatment, they have basically run out of other options, Dr. Signorelli told JNCCN 360. “Either they have the T315I resistance mutation or are thought to have disease that is unlikely to respond to a second-generation TKI,” she added.
The most challenging aspect of using ponatinib for practitioners, according to Dr. Signorelli, revolves around what to do next for these patients. Because ponatinib is usually a last-line treatment option, if the patient has a serious event, “does it mean that he or she must discontinue the only treatment that has a chance of working? Or, if ponatinib is being used to get the patient to the point where he or she can have a transplant (if there is a suitable donor), can you keep going? ‘Where do you go from there?’ is a really difficult question. Do you dose reduce? If you have already dose reduced, do you try an every-other-day schedule? Those types of decisions are difficult for patients who do not have other treatment options,” she acknowledged. If ponatinib is effective in controlling disease, a patient may be on it for years. Therefore, even if the patient is eligible for transplant, he or she would continue to take ponatinib afterward as maintenance.
The key message for community oncologists, according to Dr. Pinilla-Ibarz, is that despite 45 mg being listed in the prescribing information as the starting dose for ponatinib, “it is usually better to start with 30 mg or even 15 mg. The risks are lower, the tolerability is better, and the outcomes seem not to be jeopardized by starting with a lower dose,” he stressed. Many hematologists currently agree that ponatinib dosing should start at 30 mg, but “perhaps those with less experience prefer to stick with labeling,” Dr. Pinilla-Ibarz suggested. This pattern has been demonstrated with all of the TKIs, he noted. Imatinib, dasatinib, nilotinib, and bosutinib all were “initially recommended at higher doses, but clinical experience (and trials) demonstrated that tolerance and safety were better with lower doses, whereas efficacy was not adversely affected.”
Additionally, these questions about optimal dosing are currently being addressed in the ongoing OPTIC (ClinicalTrials.gov identifiers NCT02467270, NCT02627677) and OPUS (NCT02398825) trials. “Once dosing is optimized and effectiveness is established for lower doses, we will have the option to consider ponatinib for patients with earlier-stage disease,” Dr. Pinilla-Ibarz concluded.
Jessie R. Signorelli, PharmD, BCOP, reported no conflicts of interest.
Javier Pinilla-Ibarz, MD, has served as a consultant to and has received honoraria from Takeda, Novartis, BMS, and Pfizer.
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