25% of Patients With CLL See Disease Flare When Ibrutinib Therapy Pauses

Ibrutinib can lead to side effects, causing some physicians to consider reducing the dose or temporarily halting therapy, but that risks disease flares, a new study finds.

Even a temporary hold of ibrutinib therapy can lead to disease flares in patients with chronic lymphocytic leukemia (CLL), according to a new study.

The report, published in The Oncologist, suggests that physicians need to be aware of the risk of flares when making decisions about whether to pause the therapy.

Ibrutinib (Imbruvica), the first-in-class Bruton’s tyrosine kinase inhibitor, has led to a significant shift in the prognosis for patients with relapsed/refractory CLL. Long-term follow-up studies confirm that the drug brings a durable benefit in terms of both progression-free survival (PFS) and overall survival (OS). However, corresponding author Sameer Parikh, MBBS, of the Mayo Clinic, and colleagues noted that the benefits come with a caveat.

“Unfortunately, therapy with ibrutinib is associated with various side effects, including bleeding and hematologic and non-hematologic toxicities, as well as drug-drug interactions, that may necessitate dose modifications or interruption of treatment,” they said.

Earlier studies have suggested that discontinuation of ibrutinib leads to a risk of disease flares in patients with Waldenström’s macroglobulinemia, and the authors said evidence has been reported suggesting the same thing is true in CLL.

In an effort to better understand the risk of disease flare in CLL cases, the authors conducted a study of the Mayo Clinic’s electronic health records database.

The investigators identified 372 patients who received care for CLL at Mayo’s flagship Rochester, MN, clinic between 2012 and 2019 and were prescribed ibrutinib. They found that 143 patients (38%) had had at least 1 temporary interruption in therapy, with a median duration of interruption of 8 days. Overall, the temporary holds ranged from 1 to 59 days and the number of holds per patient ranged from 1 to 7. The most common reason for medication hold was periprocedural, Parikh and colleagues reported.

Of those who experienced a hold, disease flare was reported in one-quarter of the patients (35 people). Most of those patients (21) experienced mild flares, which were defined as constitutional symptoms only. The remaining 14 patients experienced severe flares, defined as constitutional symptoms along with exam/radiographic findings or laboratory changes. In all cases, the flares resolved once the patient was put back on ibrutinib.

The finding is notable in part because interruptions of ibrutinib are a common strategy to deal with potential side effects. While between 15-30% of patients on ibrutinib had their doses reduced, estimates of ibrutinib interruptions range from 35-65%, depending on the setting (clinical practice or clinical trial).

Yet, while less common, dose reductions do not seem to lead to disease flares.

“Across varied patient cohorts evaluating dose reductions, consistent findings of no significant differences in PFS or OS have been reported,” the investigators wrote.

By contrast, ibrutinib interruptions led to shorter event-free survival (HR 2.3; 95% CI), though they did not appear to affect overall survival.

Parikh and colleagues said patients with progressive disease at the time of the hold were more likely to experience disease flare during an interruption, as were those with 24 months or more of exposure to ibrutinib.

The investigators concluded that while ibrutinib can have significant side effects, physicians need to carefully consider their individual patient’s situation when deciding whether to pause therapy with the drug.

“It is critical for practicing hematologists and oncologists to be aware of the potential for this phenomenon during even transitory periods of treatment discontinuity, and further investigation into predictive factors and methods to mitigate risk are needed,” they said.


Hampel P, Call TG, Rabe KG, et al. Disease flare during temporary interruption of ibrutinib therapy in patients with chronic lymphocytic leukemia. Oncologist. Published online September 4, 2020. doi:10.1634/theoncologist.2020-0388

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