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Director, Georgia Cancer Center
Eminent Scholar, Georgia Research Academy
Jorge Cortes, MD, has disclosed that he has received contracted research and consulting fees from Bio-Path Holdings, Novartis, Pfizer, and Sun Pharma.
Selecting the Appropriate Treatment for Patients With CML and Comorbidities
In this commentary, I provide a background for comorbidities in chronic myeloid leukemia (CML) and discuss workup, treatment selection, and drug–drug interaction considerations in this patient population.
The median age for patients with CML is approximately 66 years but recently has been trending younger; I am seeing more patients in their 30s, 40s, and sometimes even 20s. This shift generally may be due to earlier and more frequent bloodwork and annual physicals, which means disease is likely to be detected earlier. Because of that, it is more common for patients with newly diagnosed CML to be asymptomatic, at least in the United States. In this group, CML is typically found incidentally, for example, with a blood test for other reasons, at an annual physical, or for an unrelated surgery.
CML: Comorbidities Overview
In general, comorbidities are common among patients with CML. More than 60% of patients have some comorbidity—such diabetes, hypertension, or high cholesterol—and many have more than 1 comorbidity. Studies have shown that these comorbidities tend to be even more common among patients with CML than in the general population. This understanding guides the treatment approach, informs how we monitor patients, and shifts choices for some of the other drugs patients must take. In other words, the high rate of comorbidities in CML requires comprehensive management of these patients.
Workup and Risk Assessment
It is important to conduct a bone marrow aspiration on every patient at the time of CML diagnosis. Although the diagnosis can be made without this, a patient cannot be properly staged without bone marrow analysis. If a full cytogenetic analysis is not possible, the differential in the bone marrow remains unknown, and therefore properly classifying the disease into chronic, accelerated, or blast-phase CML is not feasible. In addition, bone marrow analysis can identify other factors of prognostic significance, for example, the fibrosis that occurs in some patients.
For risk classification, I tend to use the Sokal Index for CML more than the Hasford, European Treatment and Outcome Study (EUTOS), and EUTOS Long-Term Survival (ELTS) scoring systems (Table). However, these are all important and useful classification systems with online calculators.
Table. Risk Stratification Scoring Systems in CML
Risk stratification helps not only determine prognosis for the response to treatment, but also seems to influence the probability of successful treatment discontinuation. A patient’s risk is an important feature to know at the time of diagnosis, and because scoring is based on the features at the time of diagnosis, it must be calculated at that time. In our clinic, we don’t necessarily use risk stratification for assigning treatment if all the options are available. However, in some instances, risk may be an important determinant of how to best manage a patient and identify the optimal treatment choice.
The presence of comorbidities is one of the most important determinants of treatment for a patient with CML. All available treatment options are effective, although the second-generation tyrosine kinase inhibitors (TKIs) seem to be somewhat superior to first-generation imatinib. They appear approximately equivalent, however, in the context of comorbidities.
Regarding cardiac comorbidities specifically, or risk factors for arterial occlusive events, patients with these concerns should receive the drug with the lowest documented risk of arterial occlusive events (eg, imatinib). For a patient with several of these comorbidities who is not interested in treatment discontinuation, imatinib is the safest approach. That said, the probability of achieving treatment discontinuation may be somewhat lower, but the risk of arterial occlusive events is decreased. If a second-generation TKI is chosen, bosutinib has the lowest risk of arterial occlusive events, so I tend to use that as my go to drug in these patients. Dasatinib and nilotinib have a high risk of cardiovascular events—about double compared with imatinib—so I prefer not to use them in patients with significant risk for arterial occlusive events.
For a patient who does not have these comorbidities, there are many more options, including any of the second-generation TKIs. In addition, other criteria can be used to select treatment. If patients have certain features that may predispose them to some toxicities—for example, a tendency for diarrhea due to irritable bowel syndrome or something similar—I may not use bosutinib. Likewise, in a patient with diabetes, I may not use nilotinib. Of note, the schedule of the drug may be important for long-term adherence. For some patients, taking the medication twice a day may be more difficult than once a day, as may be taking it with or without food.
Patients with other types of comorbidities, such as gastrointestinal issues or low- or moderate risk renal or liver dysfunction, can be treated effectively with imatinib, dasatinib, or nilotinib. It is possible that they will need more frequent dose adjustments or treatment interruptions, but with proper management, these patients can achieve the same good response as patients without these comorbidities. In addition, because these are patients with mild to moderate dysfunction, the starting dose can be the same as for other patients. We need to monitor the patient closely so that recommended adjustments (per the package insert) can be made carefully.
Patients who receive TKIs for their CML may experience drug–drug interactions, and those with comorbidities are at higher risk for this, as they tend to be more heavily treated. Physicians should be alert for these issues and regularly monitor patients. In some instances, the other drugs can be adjusted. For example, certain statins are more or less likely to cause a drug–drug interaction with TKIs, so selecting the drug with the lowest potential for a drug–drug interaction is important. This becomes increasingly complex with more medications and multiple comorbidities but remains an important consideration.
The type of drug–drug interaction also matters. For example, drugs such as H2 blockers or proton pump inhibitors (PPIs) will interact with a TKI and decrease its absorption. However, although this process may decrease plasma concentrations of the drug, it doesn’t increase the safety concerns. Conversely, certain other drugs may increase plasma concentrations of a TKI. That said, we typically do not use plasma levels in our clinic, as they are not easy to obtain. Healthcare professionals need to understand the potential drug–drug interactions for a given patient to determine their optimal regimen. This requires asking the patient about the drugs very intentionally; patients may not remember to mention common over-the-counter medications such as antacids, H2 blockers, or PPIs. Lastly, the risk of a drug–drug interaction is different for a drug intended for short-term use (eg, for a few days to treat an infection) than for a drug intended to be used indefinitely (eg, statins).
What challenges have you encountered in treating patients with CML and comorbidities? I encourage you to answer the polling question and join the conversation in the discussion box below.