Hematologists and patients with chronic lymphocytic leukemia (CLL) are excited about new drugs that have dramatically improved outcomes. But all drugs have side effects, and it is important to be aware of potential consequences.
Hepatotoxicity turns out to be a major concern in younger CLL patients treated with front-line idelalisib (Zydelig), according to a study presented at the recent American Society of Hematology (ASH) Annual Meeting and Exposition.1 (Idelalisib is not approved by the U.S. Food and Drug Administration for use in the front-line setting.)
Study Background
Previous reports of idelalisib-associated hepatoxicity have ranged from 2% in phase I trials to 14% in the relapsed/refractory setting. But in an ongoing phase II trial of front-line idelalisib plus ofatumumab (Arzerra), the rate of grade 3 and 4 toxicity was 52%.
In an effort to understand why this was occurring and how to manage it, Jennifer R. Brown, MD, PhD, principal investigator for the phase II trial, and colleagues analyzed the first 24 patients to enroll on this trial. Dr. Brown is Director of the CLL Center at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School, Boston.
“In the span of a 2-week rotation, I had to admit three patients to the hospital with hepatotoxicity during the lead-in phase of single-agent idelalisib. We decided to assess hepatotoxicity more fully in patients enrolled on the trial who were on single-agent idelalisib prior to the addition of ofatumumab,” explained presenting author Benjamin L. Lampson, MD, PhD, a Clinical Fellow at Dana-Farber.
“The hepatotoxicity we saw in this trial in previously untreated patients was outside the spectrum that we see in the relapse setting, in which this is readily manageable by holding drug. Our patients were rapidly worsening despite the drug being withheld. Normally that would not happen,” Dr. Brown explained. Hepatotoxicity occurred early in the course of front-line idelalisib.
Autoimmune Reaction
Median time on therapy was 7.7 months for all subjects, and median follow-up was 14.7 months. The investigators found that younger patients were significantly more likely to develop hepatotoxicity compared with older patients (P = .02.). Further, they were able to characterize it as an autoimmune reaction, since liver biopsies of these patients revealed T-cell infiltrates. Approximately 73% of 11 subjects with matched samples had decreases in regulatory T cells over time.
Twelve patients with grade 2 or higher elevated transaminases were rechallenged with idelalisib. Five were off steroids and seven were on steroids at the time of rechallenge. Of them, four (in the off-steroid group) had a recurrence of transaminase elevation within 1 to 2 days and two (in the on-steroid group) had a recurrence within 3 to 4 days.
“Patients do better if they are rechallenged while on steroids, and then we taper them. If they are not on steroids they will have a rapid recurrence,” Dr. Brown noted.
“Additionally, the number of prior therapies may be a risk factor. The phase I trial had patients with a median of five prior therapies and only a 2% risk of grade 3-4 transaminitis,” Dr. Lampson said.
“The trial was originally designed to include all ages. Of the first 24 patients, 7 were under age 65, and it turned out that these were the most severely affected, perhaps because their immune systems were intact and more competent,” Dr. Brown explained.
Cautionary Note
“Idelalisib is not approved in the front-line setting, but when using it in the relapsed/refractory setting, clinicians need to be aware of this toxicity,” she continued.
Dr. Brown said that they have slowed trial accrual and plan to enroll patients over age 65 as the trial goes on. “We are gearing our enrollment toward older patients with lower tumor burden,” she said.
The current strategy at Dana-Farber is to perform liver function tests on all patients twice weekly from weeks 3 to 16. Grade 1 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations are treated with 40 mg of prednisone. Idelalisib is withheld if grade 2 elevations develop with this strategy. For higher grade 2 and grade 3 elevations, the drug is withheld, and prednisone is ramped up to 1 mg/kg, she said.
“The take-home message is that I would be extra cautious about using idelalisib upfront in younger, more immunocompetent, and less pretreated patients. Lab monitoring is advised. Also, it is prudent to make sure that the patient does not have other hepatotoxins, such as [acetaminophen] or hepatitis virus infection,” she continued.
At Dana-Farber, statins are currently withheld in patients treated with upfront idelalisib. “Statins are hepatotoxic, and we will withhold them until we understand all the contributing factors,” she said. ■
Disclosure: The study was funded by Gilead. Dr. Brown is a consultant for Gilead and Infinity. Dr. Lampson reported no potential conflicts of interest.
Reference
1. Lampson B, Matos T, Haesook T, et al: Idelalisib given front-line for the treatment of chronic lymphocytic leukemia results in frequent and severe immune-mediated toxicities. 2015 ASH Annual Meeting. Abstract 497. Presented December 7, 2015.
