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Toxicity Concerns Exist with New Drugs for Patients with CLL

TOP - February 2016, Vol 9, No 1 - Hematologic Cancers
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Orlando, FL-New agents with novel targets have revolutionized management of chronic lymphocytic leukemia (CLL). However, all drugs have risks and benefits. At the 57th American Society of Hematology (ASH) Annual Meeting & Exposition, 3 separate presentations highlighted toxicity concerns related to idelalisib, ibrutinib, and venetoclax: hepatotoxicity with idela-lisib, drug-drug interactions with ibrutinib, and the need for careful dosing at initiation of venetoclax.

Hepatotoxicity with Frontline Idelalisib

Hepatotoxicity appears to be a significant concern with idelalisib, particularly in frontline treatment of younger patients with CLL.

Previous phase 1 studies of single-agent idelalisib reported hepatotoxicity rates ranging from 2% to 14% in the relapsed/refractory setting.1,2 More recently, investigators in an ongoing phase 2 trial of frontline therapy with idelalisib plus ofatumumab found grade 3 hepatotoxicity in 52% of the first 24 patients enrolled in the trial.

"The hepatotoxicity we observed in this trial fell outside the typical, readily manageable hepatotoxicity that we see in the relapsed setting. Our patients were rapidly worsening despite holding the drug. Normally that would not happen," explained senior investigator Jennifer Brown, MD, PhD, Director, Center for CLL, Dana-Farber Cancer Institute, and Associate Professor of Medicine, Harvard Medical School, Boston, MA. An analysis of these 24 patients showed that hepatotoxicity occurred early in the course of frontline idelalisib plus ofatumumab, and was observed mainly in younger, more fit patients.

For all subjects, median time on therapy was 7.7 months, and median follow-up was 14.7 months. Younger patients were significantly more likely to develop hepatotoxicity than older patients (P = .02); the median age of those with hepatotoxicity was 61 years versus 72 years for those without hepatotoxicity.

"We determined that this [hepatotoxicity] was associated with younger patients; the median age of the patients who had this significant hepatotoxicity was 61, whereas for the patients who did fine and had no real trouble, the median age was 72," Dr Brown told The Oncology Pharmacist in a phone interview. "This may be why this had not been observed before in 2 different company sponsored studies with idelalisib up front; both of those focused on patients over age 65."

Furthermore, liver biopsies revealed T cell infiltrates, suggesting that this was an autoimmune phenomenon. "We found that all of the patients treated with idelalisib showed a decrease in their T regulatory cells during that time, but the patients who developed the significant hepatotoxicity had a much greater decrease in their T regulatory cells," she added. "In terms of the T cell findings, no one has studied that in patients prior to us. Our report is the first report."

After the drug was withdrawn, 12 patients with grade ≥2 transaminitis were rechallenged with idelalisib. Patients on steroids at the time of rechallenge fared better. "Patients do better if they are rechallenged while on steroids, and then we taper them. If they are not on steroids they will recur rapidly," Dr Brown noted. "Idelalisib is not approved in the frontline setting, but when using it in the relapsed/refractory setting, clinicians still need to be aware of this toxicity and consider steroid use in particularly severe cases that do not resolve with holding drug," she added.

As the phase 2 trial continues, Dr Brown and colleagues are now focusing on accruing patients aged >65 years. "We are gearing our enrollment toward older patients with lower tumor burden," she said.

"The take-home message is that I would be extra cautious about using idelalisib up front on younger, more immunocompetent, and less pretreated patients. Careful lab monitoring is advised," she continued. "Also, it is prudent to make sure that the patient does not have other hepatotoxins, such as Tylenol or hepatitis virus infection."

Pharmacovigilance During Ibrutinib Therapy

Heidi Finnes, PharmD, BCOP, Clinical Pharmacy Specialist, Hematology/Oncology, Mayo Clinic, Rochester, MN, updated attendees about the importance of a pharmacologic consult for patients starting ibrutinib in routine clinical practice.

Ibrutinib is metabolized by cytochrome P450 (CYP)3A4; therefore, concurrent use with CYP3A4 inducers/inhibitors should be avoided. Ibrutinib is also associated with bleeding complications, and caution should be exercised in patients on concomitant anticoagulant and antiplatelet agents.

Concomitant CYP3A4 inhibitors (eg, ketoconazole) result in increased concentrations of ibrutinib, leading to increased toxicity; whereas concurrent CYP3A4 inducers reduce ibrutinib concentrations, and potentially lower ibrutinib efficacy, explained Dr Finnes.

"Clinical trials do not give guidance about to what to do when patients are on drugs that are inducers or inhibitors of CYP3A4, so consultation with a pharmacist is important," she noted. "Some concurrent treatments for comorbidities may result in as much as 5-fold increases or decreases in concentrations of ibrutinib."

In a study of 96 patients with CLL, of whom approximately 90% were relapsed/refractory, who initiated treatment with ibrutinib at Mayo Clinic, Rochester, 17% were on CYP3A4 inhibitors (moderate inhibitors such as fluconazole and diltiazem, and strong inhibitors such as voriconazole and clarithromycin), and 4% on CYP3A4 inducers (such as carbamazepine, rifampin, rifabutin). Furthermore, 1 in 4 patients was on an herbal supplement that affected CYP3A4 metabolism or potentially increased bleeding risk.

"Sixty-three percent of patients were on concurrent medications that can potentially increase the risk of ibrutinib toxicity and 4% were on concurrent medications that potentially reduced ibrutinib efficacy," Dr Finnes stated.

Consultation with a pharmacist enabled switching to an alternative drug, ibrutinib dose modification, and alterations of drugs for comorbidities so that patients could remain on treatment with ibrutinib and have comorbidities adequately controlled. For example, one patient taking voriconazole was switched to caspofungin to allow continuation of ibrutinib. Another patient on itraconazole continued itraconazole with a reduced dose of ibrutinib 140 mg orally once daily.

"In our 96 patients, we discontinued the offending medication in 6 patients, and in the remaining 15 an alteration of the ibrutinib dose was required so the patient could remain on ibrutinib CLL treatment," Dr Finnes told listeners. At a median follow-up of 14 months, there was no difference in ibrutinib discontinuation based on whether patients were taking inducers or inhibitors of CYP3A4.

Upon commencing ibrutinib, 9% of patients were on concomitant anticoagulants (6 warfarin and 3 low molecular weight heparin), and 34% were on antiplatelet medications (aspirin or clopidogrel). Continuation of these agents with ibrutinib must be evaluated on a case by case basis. Because of significant bleeding risk, warfarin was switched to enoxaparin in 2 patients, to aspirin in 1 patient, and discontinued in 1 patient who had completed a venous thromboembolism therapy course. Herbal supplements that alter platelet function, such as fish oil and vitamin E, were discontinued prior to starting ibrutinib. At 12 months, the risk of bleeding for patients on anticoagulant and antiplatelet agents was 12%.

In a routine clinical practice setting, 2 of 3 patients with CLL initiating ibrutinib are on concurrent medications that potentially interact with ibrutinib. With clinical pharmacist involvement, many patients are able to alter doses, or stop offending medications to safely continue ibrutinib long term.

Venetoclax Dosing Considerations

Venetoclax, an investigational oral agent that targets B-cell lymphoma 2, has shown excellent results with durable responses in patients with CLL. At the 57th ASH Annual Meeting & Exposition, a phase 2 study was presented that showed an 80% response rate in patients with CLL with 17p deletions (ie, poor prognosis patients), with durable responses.

Although venetoclax is now considered a potentially strong weapon against CLL, including patients with poor prognosis, caution should be exercised when initiating this drug, especially in patients at high risk for tumor lysis syndrome (TLS).

"In this study, venetoclax had a favorable risk-benefit profile. The risk of TLS was effectively mitigated by our careful dosing strategy, and we saw no clinical TLS," said lead investigator Stephan Stilgenbauer, MD, Department of Internal Medicine III, University of Ulm, Germany.

Because of concerns about TLS that emerged in preliminary studies, in the phase 2 study, venetoclax was given in a stepped-up dosing schedule, starting with 20 mg per day and ramped up weekly to the target dose of 400 mg at weeks ≥4. Of the 107 patients enrolled in the trial, approximately 42.1% were considered high risk for TLS.


1. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123:3390-3397.
2. Coutre S, Barrientos JC, Brown JR, et al. Safety of idelalisib in B-cell malignancies: integrated analysis of eight clinical trials. Presented at: 2015 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago, IL.

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Last modified: July 22, 2021