Ibrutinib Surpasses Ofatumumab as Second-Line Treatment of Chronic Lymphocytic Leukemia

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John C. Byrd, MD

Ibrutinib vs Ofatumumab in CLL

Ibrutinib (Imbruvica) significantly improved progression-free survival, overall survival, and response when compared with ofatumumab (Arzerra) as second-line treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) in the phase III RESONATE study. The study results were presented at the 50th ASCO Annual Meeting and published online in The New England Journal of Medicine to coincide with the ASCO presentation.

“Ibrutinib beat a standard comparator in CLL for the first time,” stated John C. Byrd, MD, principal investigator of the study and Director of Hematology at The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus.

The impact of ibrutinib was similar regardless of what types of pretreatment patients had received and molecular features of the disease. “The improvement in survival remained significant despite the crossover of 57 patients who had disease progression on ofatumumab,” Dr. Byrd said.

Ibrutinib is a first-in-class irreversible inhibitor of Bruton’s tyrosine kinase, and the drug has been given Breakthrough Therapy designation by the U.S. Food and Drug Administration.

The RESONATE study randomly assigned previously treated CLL/SLL patients in a 1:1 ratio to oral ibrutinib (n = 195) or to intravenous ofatumumab (n = 196). Median follow-up was 9.4 months. The study included patients with a short response to first-line therapy, elderly patients (over age 65), and those with deletions in 17p; these patients have poor outcomes and limited treatment options, he said.

Key Results

“At a median follow-up of 9.4 months, 86% of patients on ibrutinib had durable responses and were continuing on treatment with minimal side effects. This is remarkable, especially considering that standard CLL therapies typically produce a 35% to 40% response rate,” Dr. Byrd commented.

At 6 months, 83% of the ibrutinib arm experienced progression-free survival compared with 49% of those on the ofatumumab arm. At the time the data were presented, median progression-free survival had not yet been reached in the ibrutinib arm vs 8.08 months in the ofatumumab arm (P < .0001). This represents a 78% reduction in the risk of progression with ibrutinib.

The impact on progression-free survival was observed in all patient groups, including the elderly and those with deletions in chromosome 17p, Dr. Byrd said. Richter’s transformation, which is a concern, occurred in only two patients in each arm.

While median overall survival had not yet been reached in either treatment arm, the investigators found a significant improvement in overall survival for ibrutinib vs ofatumumab. There was a 57% reduction in risk of death for the ibrutinib arm (P < .0049). At 12 months, the overall survival rate was 90% with ibrutinib vs 81% with ofatumumab.

Treatment with ibrutinib led to a 78% reduction in the risk of disease progression or death vs ofatumumab treatment. Overall response rate was 42.6% for ibrutinib vs 4.1% for ofatumumab (P < .001). These positive results were achieved despite the crossover of 57 patients from ofatumumab to ibrutinib, Dr. Byrd commented.

The safety profiles of both drugs were acceptable, with similar rates of major hemorrhage and renal toxicities, and higher rates of atrial fibrillation with ibrutinib and neuropathy with ofatumumab. Ibrutinib does carry the risk of diarrhea, (48% vs 18% with ofatumumab), but it is modest and manageable in most patients, he said. Other nonhematologic adverse events included fatigue, pyrexia, and nausea in the ibrutinib group and cough in the ofatumumab group.

For Most Relapsed, Refractory CLL

“If I were a patient with CLL, I would want this drug. In the relapsed and refractory setting after one prior therapy, there is no good reason not to give this drug outside of a few circumstances; those exceptions include patients on warfarin, because of an early safety signal regarding bleeding, hematomas, inflammatory bowel disease, and sarcoidosis,” Dr. Byrd commented. “The findings of phase II and the confirmatory phase III study show ibrutinib should be used for all relapsed, refractory CLL. Patients can go back to regular life and be productive.”

Looking Ahead

Dr. Byrd told The ASCO Post that ibrutinib is about to undergo phase III testing in mantle cell lymphoma with bendamustine (Treanda)/rituximab (Rituxan) as the comparator. Ibrutinib is also in phase III study as first-line therapy for CLL.

Envisioning how all the new agents for CLL will be deployed, Dr. Byrd said younger patients could be treated with several of the active drugs for CLL to achieve remission; these include ibrutinib, idelalisib, ABT-199, and obinutuzumab (Gazyva). Older, more infirm patients with a life expectancy of 2 to 3 years could receive ibrutinib because of its benign side-effect profile. ■

Disclosure: Dr. Byrd has received research funding from Pharmacyclics. For full disclosures of all study authors, visit


1. Byrd JC, Brown JR, O’Brien SM, et al: Results from the phase III RESONATE trial. ASCO Annual Meeting. Abstract LBA 7008. Presented June 3, 2014.


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