Ibrutinib Interruption Tied to Worse Outcomes in CLL

Kate Johnson

April 01, 2020

Among patients with chronic lymphocytic leukemia (CLL) being treated with the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica, Pharmacyclics), interruptions in dosing for any reason were associated with a shorterning of event-free survival (EFS) and overall survival (OS).

The findings suggest that "patients who are able to adhere to treatment better may derive more benefit," say the authors of a retrospective analysis published online March 18 in Cancer Medicine.

Adherence to therapy "not only during the first 8 weeks but during the entire course of therapy may impact outcomes," state the authors, led by Sameer A. Parikh, MD, from the Mayo Clinic, Rochester, Minnesota.

However, they add that "these findings should be interpreted with caution since patients who are able to adhere to therapy are generally those who are able to tolerate treatment better, and have no major comorbidities."

The authors note that their results confirm observations from other "real-world" analyses that indicate that most patients who stop taking ibrutinib do so because of toxicity, illustrating the challenges associated with this continuous oral therapy.

"This latter finding has major implications for clinical trial design where combination therapies with fixed duration of treatment that achieve deep remission may be more desirable than chronic long‐term treatment," they add.

Study Details

Parihk and colleagues used the Mayo Clinic database of CLL patients to identify those who received ibrutinib therapy outside the context of a clinical trial (ie, via commercial supply).

They analyzed all reasons for dose modifications and temporary interruptions in therapy and then correlated these events with outcomes.

Among the 299 patients included, 162 (78%) had relapsed/refractory CLL, and 47 (22%) had progressive, treatment‐naive CLL.

A total of 122 (58%) patients received a standard starting dose of ibrutinib (420 mg daily). The remaining 87 (42%) patients initiated therapy at lower daily oral doses of 280 or 140 mg (n = 35 and n = 48, respectively) or 140 mg every other day (n = 4).

During the 281 person‐years of treatment, the estimated unadjusted 6‐month, 1‐year, and 2‐year risks for ibrutinib interruption (first event only) were 28%, 40%, and 57%, respectively, they report. The median time to first dose interruption was 19 months.

After a median follow-up of 24 months, temporary dose interruption of ibrutinib (hazard ratio [HR], 2.37, 95% confidence interval [CI], 1.29 – 4.36; P = .006) and TP53 disruption (HR, 1.81; 95% CI, 1.01 – 3.27; P = .048) were associated with a shorter EFS after adjusting for age, sex, Rai stage, prior treatment status, and initial ibrutinib dose.

In addition, after adjusting for age, prior treatment status, and initial ibrutinib dose, TP53 disruption (HR, 2.38; 95% CI, 1.19 – 4.76; P = .015) was associated with shorter OS. The effects of temporary dose interruption did not reach the threshold of statistical significance (HR, 1.98; 95% CI, 0.98 4.00; P = .06), they report.

"Although a lower starting dose in a subset of patients did not seem to impact outcomes in our patients, longer term follow‐up in larger cohorts of patients (preferably done in the context of a clinical trial) are necessary before this may be considered as standard practice. Therefore, at the current time, we recommend all patients receive therapy according to the manufacturer's prescribing information," they write.

The study was supported by Pharmacyclics. Parikh has received institutional research funding from Pharmacyclics, MorphoSys, Janssen, AbbVie, AstraZeneca, Genentech, GlaxoSmithKline, Celgene, and Ascentage Pharma, for which he is an investigator. He has also participated in advisory board meetings of Pharmacyclics, AstraZeneca, Gilead, and AbbVie (he was not personally compensated for his participation). Other authors have also disclosed relevant financial relationships, as listed in the original article.

Cancer Med. Published online March 18, 2020. Full text

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