Medication Reconciliation in CLL: Considerations for Use of BTK Inhibitors

Carmen Nobre

Medication reconciliation strategies are fundamental to maximizing pharmacotherapeutic benefits and minimizing the incidence of adverse drug events. And we know, as oncology providers, that outpatient cancer treatment presents significant challenges. As the care of CLL [chronic lymphocytic leukemia] trends toward greater use of targeted therapies that can be taken orally at home, we need to be increasingly mindful of potential drug-drug interactions and use appropriate tools and best practices to avoid these wherever possible.

Amy Goodrich

That’s certainly true, Carmen, especially for our patients with CLL. Since they tend to be older, with the majority in their 70s, issues like poor general overall health, comorbidities, and polypharmacy all come into play. Let's talk today about medication reconciliation in the management of CLL, with a focus on our patients who are undergoing treatment with Bruton's tyrosine kinase [BTK] inhibitors. What are some of the key pharmacologic effects of treatment with BTK inhibitors as a drug class?

Carmen Nobre

We should start our discussion by reviewing just a bit of the background information that we highlighted in our first Expert Conversation for JADPRO’s CLL series, on understanding the role of BTK inhibitors in B-cell malignancies like CLL. BTK is a kinase that regulates B-cell responses, but mutations in the BTK gene can lead to absent or abnormal BTK protein, along with reductions in the number of circulating B cells and reduced ability to fight infection and cancer cell proliferation.

By blocking BTK with small-molecule inhibitors in patients with B-cell malignancies, BTK inhibitors help to induce apoptosis by blocking the B-cell receptor signaling essential for leukemia and lymphoma cell survival.

But there are differences in off-target effects between the first-generation BTK inhibitor, ibrutinib, and the second-generation agents, such as acalabrutinib, which is approved in CLL, and zanubrutinib, which is approved for patients with mantle cell lymphoma but is currently under investigation for treatment of CLL.

Amy Goodrich

Right, Carmen, and it’s good to be aware of these different off-target effects of first-generation versus second-generation BTK inhibitors when discussing targeted therapy options with our patients and educating them on possible adverse events. For example, ibrutinib, in addition to its inhibition of BTK, inhibits the tyrosine kinases Tec and Src, as well as the receptor tyrosine kinase EGFR [epidermal growth factor receptor]. As a result, in our CLL patients treated with ibrutinib we see adverse events such as bleeding or bruising due to Tec and Src inhibition or atrial fibrillation, again due to Tec inhibition. We may also see rash or diarrhea due to EGFR inhibition. In comparison, the second-generation BTK inhibitors acalabrutinib and zanubrutinib inhibit these off-target kinases only minimally, resulting in a decreased incidence of those adverse events I just mentioned. Other key differences we see in the drug-related adverse events between agents include a higher incidence of hypertension in patients taking ibrutinib and more headaches occurring in patients taking acalabrutinib.^1,2

Carmen Nobre

Given the risk of these ADEs [adverse drug events] with BTK inhibitors, what are you looking for in the patient history and assessment, Amy?

Amy Goodrich

We review the patient's overall health status and history of other comorbidities such as hypertension, heart failure, and obesity. These comorbidities in particular could potentially put a patient at risk of developing new-onset AFib [atrial fibrillation]. Including a comprehensive medication review in this assessment allows us to identify potential medication-related problems. Since BTK inhibitors are metabolized by the liver and are primarily CYP3A4 substrates, can you talk about the implications for potential drug reactions?

Carmen Nobre

Sure, Amy. Educating patients and providers about medications that may impact BTK inhibitor therapy is key. Just as an example to illustrate why, a Mayo Clinic multicenter evaluation of 118 CLL patients in a real-world setting found two-thirds of these patients were taking concomitant medications that potentially interact with ibrutinib and affect its metabolism.³ This underscores how important it is to recognize when patients are on concurrent therapies that may inhibit CYP3A while they are on BTK inhibitors, since of course CYP3A inhibition may significantly increase systemic exposure to the BTK inhibitor, translating to a greater likelihood of toxicity. Patients also may be taking medications that induce CYP3A, thus reducing systemic exposure to the BTK inhibitor and resulting in a loss of efficacy.

The most common CYP3A4 inhibitors of interest often include several antihypertensive and antifungal agents, such as diltiazem and posaconazole. Some key CYP3A4 inducers include phenytoin, rifampin, carbamazepine, and St. John's wort.

Amy Goodrich

Carmen, can you highlight some strategies for avoiding CYP3A interactions with BTK inhibitors?

Carmen Nobre

Prescribing information for the individual BTK inhibitors provides guidance on patient management and dosing modifications, to help avoid potentially harmful interactions with concurrent patient medications. For example, if a patient under treatment with acalabrutinib is receiving concurrent treatment with a moderate CYP3A4 inhibitor, the prescribing information recommends reducing the acalabrutinib dosage from 100 mg twice a day to dosing it at 100 mg once a day.²

Another example is with ibrutinib, which has varying recommendations based on indication and a specific interacting agent. To help explain, we'd want to consider decreasing ibrutinib from 420 mg daily to 140 mg daily when the patient is using voriconazole concurrently. However, we may need to consider further reduction of ibrutinib to 70 mg daily if the patient were to use posaconazole delayed-release tablets.¹ This is a question that I’m often asked in clinic.

Amy Goodrich

Right, and I know that I have asked you those questions very frequently, Carmen! It's just so helpful to have a pharmacist, someone who really is well versed on this, available to help guide decisions and flag these potential drug-drug interactions. Are there other important considerations for bioavailability and potential drug interactions?

Carmen Nobre

We know that ibrutinib may inhibit P-glycoprotein transporters and increase concentrations of drugs with a narrow therapeutic index—an example here is digoxin. Separately, acalabrutinib requires an acidic environment for optimal absorption. Its solubility is decreased in the presence of increased gastric pH.²

Amy Goodrich

Importantly, concomitant treatment with proton pump inhibitors [PPIs] should be avoided in patients on acalabrutinib because studies have shown that PPIs significantly reduce acalabrutinib's bioavailability, and we know research into this effect is ongoing. For instance, a 2019 study looked at a physiologically based pharmacokinetic model to evaluate effects of both acidic beverages and PPIs on acalabrutinib bioavailability under a variety of conditions.⁴ In terms of clinical studies, just as an example, a Baltimore-based phase 2 clinical trial [ClinicalTrials.gov identifier NCT04488016] is now under way in healthy subjects to assess the pharmacokinetics and bioavailability of acalabrutinib taken in capsule versus tablet form with or without food and with or without coadministration of the PPI rabeprazole. So findings from current research could potentially even further inform our treatment decisions regarding medication reconciliation in the context of BTK inhibitor use in CLL.

Carmen Nobre

Similarly, when I am doing my medication reconciliations with patients, and I find that they are taking an acid-suppressing medication, I try to determine what the indication for that medication is, and if it warrants continuation of therapy. If they're on a PPI inhibitor, depending on the reason that they're on the medication, it may be beneficial to consider switching to something like an H2 blocker or even just a simple antacid to provide relief to a patient who does need some kind of antacid therapy. With this approach, it may be easier to time the medication use around the use of acalabrutinib to allow for an acidic environment that will optimize acalabrutinib absorption and thus avoid or minimize the potential interaction.

I also have risk-benefit discussions with providers in cases of patients who may continue to benefit from continuation of their PPI, but who also need concurrent therapy with acalabrutinib. Really our concern here is that reduced absorption of acalabrutinib could begin to impact its efficacy, so we monitor these patients closely to ensure that the patient is still having an optimal response to their therapy.

Amy Goodrich

As healthcare providers we must also educate patients taking acalabrutinib about medication timing if there may be potential use of any H2-receptor blockers. Patients should take their acalabrutinib 2 hours before taking their H2 receptor–blocker medications. Patients should also separate dosing of antacids and acalabrutinib by at least 2 hours.

It's also important to review any use of vitamins, supplements, and other over-the-counter [OTC] agents that people may be taking. What else do you highlight in your patient education discussions?

Carmen Nobre

I start with asking patients specifically about herbals or supplements that they may be using. Sometimes these seemingly harmless supplements can add to the risk of treatment toxicity. One common example I encounter is the use of turmeric or curcumin as a supplement. This is an important one because, in high doses, turmeric and curcumin can increase the risk of bleeding and inhibit CYP3A4.

I also review the use of over-the-counter analgesics. I’ll recommend using acetaminophen, if needed, for things like headache or other minor pains. I emphasize to my patients that they should avoid NSAIDs [nonsteroidal anti-inflammatory drugs], such as ibuprofen, since these may increase the risk of bleeding. Another point I'll make here is to also discuss foods, because some foods may contain moderate inhibitors of CYP3A4. Our most common offenders in this regard include grapefruit, grapefruit juice, and Seville oranges.

In terms of identifying use of other over-the-counter medications, I'll ask patients what OTC drugs they're taking. If they are unable to remember during the time of their visit, I may follow up with a phone call or provide them with some way of contacting me; that way, the patient can go home, make a complete list of whatever medications they may be using at the time, and send the list over to me so I can further review it. The point is, sometimes it's not feasible to accomplish medication reconciliation in a single sitting, but having a way to stay in contact with the patient to obtain this information, as well as having access to information from pharmacists and other healthcare professionals, provides a more complete picture of the patient's overall care.

For communicating with patients about contraindications for specific over-the-counter or other medications while they’re taking a BTK inhibitor, there is no single list that I share. I simply recommend that the patient just let us know if they're about to start treatment with any new medications or if they're considering using new supplements, such as herbal agents. Amy, as I’ve mentioned, optimal management of CLL for patients receiving BTK inhibitors depends on multidisciplinary collaboration. Can you talk about best practices and highlight how CLL care is coordinated at Johns Hopkins?

Amy Goodrich

I’d be glad to, Carmen. As you said, following best practices and coordinating care are critical to achieving successful outcomes for our patients with CLL, as well as patients with other B-cell malignancies. These patients often receive treatment in a variety of settings. They may be in an infusion center; an ambulatory clinic; and more often now, at home, given the availability of oral agents such as our BTK inhibitors and BCL-2 inhibitors. Because increasing numbers of patients with CLL are receiving oral therapy at home, continued monitoring, toxicity assessments, and monitoring for adherence are all critical to ensure treatment success and optimize outcomes.

Oral chemotherapy management programs provide a solid foundation to improve our patients’ understanding of, and adherence to, their treatment regimen; added benefits of these programs include more timely medication access plus provider identification of clinically significant adverse events and drug-drug interactions.  Could you tell us a bit more about your role in this process?

Carmen Nobre

Sure! As a clinical pharmacy specialist, I review therapies with all patients newly starting on oral anticancer agents, such as BTK inhibitors and BCL-2 inhibitors. I will assess the dose of these agents in regard to their indication, as well as factors specific to the individual patient, including organ function. I also complete medication reconciliations. I assess for drug-drug interactions and any relevant drug administration concerns.

From there, I also counsel patients on their new therapy and will complete follow-up phone calls, sometimes even joining on patient visits to help follow up on toxicity and adherence management. We also have a dedicated team here at Hopkins that helps with any needed insurance prior authorizations, or medication access issues, which are often the biggest barrier to care with these new medications.

Amy Goodrich

Given the times we’re living in as healthcare providers right now, I want to add that I have sometimes found it very difficult to get good medication lists from patients in this age of COVID-19. The problem is that folks are more often coming to clinic alone and may be overwhelmed, and perhaps it’s their caregiver or family member who is primarily managing their medications. So medication reconciliation has become an even greater challenge during the pandemic and oftentimes does require reaching out to others besides the patient, just to make sure we understand what drugs a patient is taking. Of course, we're all busy in clinic and we've got competing demands. The medication reconciliation process has definitely required more attention, but as you say, if we don't do this right, we potentially are not getting the treatment efficacy that we want to achieve for our patients.

I also want to circle back to what you said earlier, Carmen, and emphasize that our multidisciplinary approach—and I’m sure this is essential not just at Hopkins but in many other oncology settings—has absolutely helped us to address the different complexities of caring for our patients. I think the key is having a process, with the understanding that who's involved varies from practice to practice. Just having an integrated team and a multidisciplinary team is important. Continued integration of this team approach has helped us to get patients on drug quicker, to educate patients better, and to identify toxicities and other treatment issues, thereby really maximizing the quality of care. With ongoing clinical trials and new agents on the horizon, we absolutely will continue to learn how best to sequence these drugs and optimize therapeutic outcomes for our patients.