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Patients with early-stage, high-risk chronic lymphocytic leukemia (CLL) failed to achieve an overall survival (OS) benefit when treated with ibrutinib (Imbruvica) compared with placebo, according to results from the randomized .

While event-free survival (EFS), progression-free survival (PFS), and time to next treatment (TTNT) were significantly longer for patients treated with ibrutinib compared with placebo, no significant difference was seen in median OS between the two groups at a median follow-up of 69.3 months (not reached in either arm, HR 0.791, 95% CI 0.358-1.748, P=0.562), reported Petra Langerbeins, MD, of the University of Cologne in Germany.

Moreover, there was no significant difference between the treatment the placebo groups and a third cohort of patients with low-risk CLL who were allocated to a "watch and wait" strategy, Langerbeins said during her presentation at the European Hematology Association annual congress in Frankfurt, Germany.

"Patients with early-stage CLL are managed by watch and wait as early chemo or chemoimmunotherapy interventions have failed to demonstrate a survival advantage as compared to delaying treatment until disease progression," Langerbeins said in explaining the rationale behind . "However, it has not been clear whether patients with certain risk features might benefit from an early targeted intervention."

The estimated OS rates at 5 years for patients treated with ibrutinib and placebo were 93.3% and 93.6%, respectively, while the estimated 10-year OS rates were 89.8% in the ibrutinib group, 86.5% in the placebo group, and 95.3% in the watch and wait cohort.

"The median survival is fantastic for untreated patients with risk features, and is estimated to be over 20 years," Langerbeins said. "So, with this, I believe it is fair to conclude that watch and wait should remain the standard of care, even in the era of targeted drugs."

Median EFS was not reached with ibrutinib versus 51.6 months with placebo (HR 0.276, 95% CI 0.188-0.407, P<0.001), with 5-year EFS rates of 78.2% and 48.0%, respectively. Median PFS was not reached with ibrutinib versus 14.0 months with placebo (HR 0.174, 95% CI 0.122-0.246, P<0.001), with 5-year PFS rates of 73.9% and 23.7%, respectively.

The overall response rate was 72.5% with ibrutinib versus 5% with placebo. The proportion of patients who received subsequent treatments was 15.9% in the ibrutinib arm and 43.6% in the placebo arm. Median TTNT was not reached in the ibrutinib arm versus 68.5 months in the placebo arm (HR 0.244, 95% CI 0.156-0.380, P<0.001).

Adverse events of any grade were observed in 99.4% of patients in both the ibrutinib and placebo groups, while grade 3-5 adverse events occurred in 71.8% and 66.1%, respectively. Serious adverse events occurred in 9.9% of patients in the ibrutinib group and 14.9% in the placebo group.

Second malignancies of any grade were reported in 12.9% of patients in the ibrutinib group, 21.4% in the placebo arm, and 9.9% among watch and wait patients. Grade 5 second malignancies were reported in 1.2%, 3%, and 1.3% of the three groups, respectively.

"Adverse events of clinical interest included the most typical ibrutinib-associated side effects," Langerbeins noted, with those events seen in 80% of patients in the ibrutinib group versus 52% in the placebo group.

Importantly, the rate of bleeding events was 36.5% in the ibrutinib group versus 14.9% in the placebo group, while cardiac arrhythmias occurred in 22.4% and 9.5% of patients, respectively.

The median number of treatment cycles was 39 in the ibrutinib arm and 27.5 in the placebo arm, with early treatment discontinuation occurring in 61.8% and 81% of patients. The main reasons for discontinuation were adverse events in the ibrutinib group and progressive disease in placebo patients.

Langerbeins and colleagues initiated the CLL12 trial 10 years ago at 89 participating academic and community hospitals and oncology practices in Germany.

The trial included 363 patients with asymptomatic, treatment-naive Binet stage A CLL, who were at increased risk of progression. They were assigned 1:1 to ibrutinib 420 mg daily or placebo. Patients with low-risk CLL (n=152) were allocated to the watch and wait group.

The median age of patients in the ibrutinib and placebo groups was 64 years, and the majority of patients were men (75% and 70%, respectively). Median age was 57 years in the watch and wait group, and 44% were men.

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