Ibrutinib boosts survival of relapsed/refractory CLL

CHICAGO – For the first time an oral drug, ibrutinib, has been shown to significantly improve both progression-free and overall survival of patients with relapsed or refractory chronic lymphocytic leukemia, compared with a systemic agent.

The first interim analysis of a phase III randomized trial showed that 1-year overall survival for patients with previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) assigned to receive ibrutinib (Imbruvica) was 90%, compared with 81% for patients assigned to ofatumumab (Arzerra).

The hazard ratio (HR) for death for patients assigned to ibrutinib was 0.43 (P = .005), reported lead author Dr. John Byrd, professor of medicine at the Ohio State University Comprehensive Cancer Center, Columbus, at a media briefing at the annual meeting of the American Society of Clinical Oncology.

The median time to progression for patients on ibrutinib had not been reached, compared with 8.08 months for those on ofatumumab. At 15 months follow-up, the median progression-free survival (PFS) was 8.4 months in the ofatumumab group vs. not reached for patients on ibrutinib.

Ibrutinib reduced by 78% the risk of disease progression or death, compared with ofatumumab, Dr. Byrd noted.

The overall survival advantage shown with ibrutinib persisted even after 57 patients who had disease progression while on ofatumumab were crossed over to ibrutinib, Dr. Byrd said.

"These patients who have a short response to first-line therapy, or who are elderly, have very few treatment options that induce durable remissions. Identifying new therapies in this patient population, particularly those that extend survival, is very important," he said.

"The issue now is how to best use the drug and how to most effectively move this into the front-line setting. This is a transformative drug," commented Dr. Olatoyosi Odenike, a leukemia specialist from the University of Chicago, who was not involved in the study.

Dr. Gregory A. Masters of Jefferson Medical College, Philadelphia, and the Helen F. Graham Cancer Center in Newark, Del., who moderated the briefing, but was not involved in the study, echoed those sentiments.

"I think this drug’s efficacy may in fact transform the treatment of CLL, potentially replacing more toxic chemotherapy," he said.

B-cell signaling inhibitor

Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase, an enzyme essential for B-cell receptor signaling and adhesion that is present in many types of B-cell malignancies. Based on the results of phase II studies, ibrutinib received Food and Drug Administration approval for relapsed mantle cell lymphoma in November 2013 and for CLL in February 2014.

Ofatumumab, a CD20 inhibitor, was approved for the treatment of CLL based on a single group study in which patients whose disease was resistant to fludarabine and alemtuzumab had an overall response rate of 58%.

In the RESONATE trial, Dr. Byrd and his colleagues enrolled 391 patients with relapsed or refractory CLL or SLL and randomly assigned them to receive either oral ibrutinib 420 mg once daily until disease progression or unacceptable toxicity (195 patients) or to IV ofatumumab at an initial dose of 300 mg followed by 11 doses at 2,000 mg (196 patients).

At a median follow-up of 9.4 months, the median duration of PFS, the primary endpoint, had not been reached in ibrutinib-treated patients (88% of whom had PFS at 6 months), compared with 8.1 months for patients treated with ofatumumab.

In all, 42.6% of patients on ibrutinib had a partial response rate, compared with 4.1% of those on ofatumumab. In addition, 20% of patients on ibrutinib had a partial response with lymphocytosis. Lymphocytosis occurred in 69% of all patients treated with ibrutinib. The investigators did not consider lymphocytosis to be disease progression, and the condition resolved in 77% of these patients during follow-up.

Nonhematologic adverse events occurring in at least 20% of patients included diarrhea, fatigue, pyrexia, and nausea in patients on ibrutinib, and fatigue, infusion-related reactions, and cough in those on ofatumumab.

In all, 4% of patients on ibrutinib and 5% on ofatumumab discontinued the assigned drug because of adverse events.

Richter’s transformation – CLL evolving into an aggressive, rapidly growing large-cell lymphoma – occurred in two patients in each treatment arm. One patient on ibrutinib developed prolymphocytic leukemia.

Dr. Byrd noted that the improved PFS, overall survival, and response rates with ibrutinib were seem across all patient subgroups, including patients who were resistant to chemoimmunotherapy and those with the notorious chromosome 17p13.1 deletion.

Ibrutinib is currently being explored in patients with previously untreated CLL or SLL. The study was supported by Pharmacyclics. Dr. Byrd disclosed receiving research funding and serving as an unpaid advisor to the company. Dr. Odenike and Dr. Masters reported having no relevant disclosures.

CHICAGO – For the first time an oral drug, ibrutinib, has been shown to significantly improve both progression-free and overall survival of patients with relapsed or refractory chronic lymphocytic leukemia, compared with a systemic agent.

The first interim analysis of a phase III randomized trial showed that 1-year overall survival for patients with previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) assigned to receive ibrutinib (Imbruvica) was 90%, compared with 81% for patients assigned to ofatumumab (Arzerra).

The hazard ratio (HR) for death for patients assigned to ibrutinib was 0.43 (P = .005), reported lead author Dr. John Byrd, professor of medicine at the Ohio State University Comprehensive Cancer Center, Columbus, at a media briefing at the annual meeting of the American Society of Clinical Oncology.

The median time to progression for patients on ibrutinib had not been reached, compared with 8.08 months for those on ofatumumab. At 15 months follow-up, the median progression-free survival (PFS) was 8.4 months in the ofatumumab group vs. not reached for patients on ibrutinib.

Ibrutinib reduced by 78% the risk of disease progression or death, compared with ofatumumab, Dr. Byrd noted.

The overall survival advantage shown with ibrutinib persisted even after 57 patients who had disease progression while on ofatumumab were crossed over to ibrutinib, Dr. Byrd said.

"These patients who have a short response to first-line therapy, or who are elderly, have very few treatment options that induce durable remissions. Identifying new therapies in this patient population, particularly those that extend survival, is very important," he said.

"The issue now is how to best use the drug and how to most effectively move this into the front-line setting. This is a transformative drug," commented Dr. Olatoyosi Odenike, a leukemia specialist from the University of Chicago, who was not involved in the study.

Dr. Gregory A. Masters of Jefferson Medical College, Philadelphia, and the Helen F. Graham Cancer Center in Newark, Del., who moderated the briefing, but was not involved in the study, echoed those sentiments.

"I think this drug’s efficacy may in fact transform the treatment of CLL, potentially replacing more toxic chemotherapy," he said.

B-cell signaling inhibitor

Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase, an enzyme essential for B-cell receptor signaling and adhesion that is present in many types of B-cell malignancies. Based on the results of phase II studies, ibrutinib received Food and Drug Administration approval for relapsed mantle cell lymphoma in November 2013 and for CLL in February 2014.

Ofatumumab, a CD20 inhibitor, was approved for the treatment of CLL based on a single group study in which patients whose disease was resistant to fludarabine and alemtuzumab had an overall response rate of 58%.

In the RESONATE trial, Dr. Byrd and his colleagues enrolled 391 patients with relapsed or refractory CLL or SLL and randomly assigned them to receive either oral ibrutinib 420 mg once daily until disease progression or unacceptable toxicity (195 patients) or to IV ofatumumab at an initial dose of 300 mg followed by 11 doses at 2,000 mg (196 patients).

At a median follow-up of 9.4 months, the median duration of PFS, the primary endpoint, had not been reached in ibrutinib-treated patients (88% of whom had PFS at 6 months), compared with 8.1 months for patients treated with ofatumumab.

In all, 42.6% of patients on ibrutinib had a partial response rate, compared with 4.1% of those on ofatumumab. In addition, 20% of patients on ibrutinib had a partial response with lymphocytosis. Lymphocytosis occurred in 69% of all patients treated with ibrutinib. The investigators did not consider lymphocytosis to be disease progression, and the condition resolved in 77% of these patients during follow-up.

Nonhematologic adverse events occurring in at least 20% of patients included diarrhea, fatigue, pyrexia, and nausea in patients on ibrutinib, and fatigue, infusion-related reactions, and cough in those on ofatumumab.

In all, 4% of patients on ibrutinib and 5% on ofatumumab discontinued the assigned drug because of adverse events.

Richter’s transformation – CLL evolving into an aggressive, rapidly growing large-cell lymphoma – occurred in two patients in each treatment arm. One patient on ibrutinib developed prolymphocytic leukemia.

Dr. Byrd noted that the improved PFS, overall survival, and response rates with ibrutinib were seem across all patient subgroups, including patients who were resistant to chemoimmunotherapy and those with the notorious chromosome 17p13.1 deletion.

Ibrutinib is currently being explored in patients with previously untreated CLL or SLL. The study was supported by Pharmacyclics. Dr. Byrd disclosed receiving research funding and serving as an unpaid advisor to the company. Dr. Odenike and Dr. Masters reported having no relevant disclosures.

CHICAGO – For the first time an oral drug, ibrutinib, has been shown to significantly improve both progression-free and overall survival of patients with relapsed or refractory chronic lymphocytic leukemia, compared with a systemic agent.

The first interim analysis of a phase III randomized trial showed that 1-year overall survival for patients with previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) assigned to receive ibrutinib (Imbruvica) was 90%, compared with 81% for patients assigned to ofatumumab (Arzerra).

The hazard ratio (HR) for death for patients assigned to ibrutinib was 0.43 (P = .005), reported lead author Dr. John Byrd, professor of medicine at the Ohio State University Comprehensive Cancer Center, Columbus, at a media briefing at the annual meeting of the American Society of Clinical Oncology.

The median time to progression for patients on ibrutinib had not been reached, compared with 8.08 months for those on ofatumumab. At 15 months follow-up, the median progression-free survival (PFS) was 8.4 months in the ofatumumab group vs. not reached for patients on ibrutinib.

Ibrutinib reduced by 78% the risk of disease progression or death, compared with ofatumumab, Dr. Byrd noted.

The overall survival advantage shown with ibrutinib persisted even after 57 patients who had disease progression while on ofatumumab were crossed over to ibrutinib, Dr. Byrd said.

"These patients who have a short response to first-line therapy, or who are elderly, have very few treatment options that induce durable remissions. Identifying new therapies in this patient population, particularly those that extend survival, is very important," he said.

"The issue now is how to best use the drug and how to most effectively move this into the front-line setting. This is a transformative drug," commented Dr. Olatoyosi Odenike, a leukemia specialist from the University of Chicago, who was not involved in the study.

Dr. Gregory A. Masters of Jefferson Medical College, Philadelphia, and the Helen F. Graham Cancer Center in Newark, Del., who moderated the briefing, but was not involved in the study, echoed those sentiments.

"I think this drug’s efficacy may in fact transform the treatment of CLL, potentially replacing more toxic chemotherapy," he said.

B-cell signaling inhibitor

Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase, an enzyme essential for B-cell receptor signaling and adhesion that is present in many types of B-cell malignancies. Based on the results of phase II studies, ibrutinib received Food and Drug Administration approval for relapsed mantle cell lymphoma in November 2013 and for CLL in February 2014.

Ofatumumab, a CD20 inhibitor, was approved for the treatment of CLL based on a single group study in which patients whose disease was resistant to fludarabine and alemtuzumab had an overall response rate of 58%.

In the RESONATE trial, Dr. Byrd and his colleagues enrolled 391 patients with relapsed or refractory CLL or SLL and randomly assigned them to receive either oral ibrutinib 420 mg once daily until disease progression or unacceptable toxicity (195 patients) or to IV ofatumumab at an initial dose of 300 mg followed by 11 doses at 2,000 mg (196 patients).

At a median follow-up of 9.4 months, the median duration of PFS, the primary endpoint, had not been reached in ibrutinib-treated patients (88% of whom had PFS at 6 months), compared with 8.1 months for patients treated with ofatumumab.

In all, 42.6% of patients on ibrutinib had a partial response rate, compared with 4.1% of those on ofatumumab. In addition, 20% of patients on ibrutinib had a partial response with lymphocytosis. Lymphocytosis occurred in 69% of all patients treated with ibrutinib. The investigators did not consider lymphocytosis to be disease progression, and the condition resolved in 77% of these patients during follow-up.

Nonhematologic adverse events occurring in at least 20% of patients included diarrhea, fatigue, pyrexia, and nausea in patients on ibrutinib, and fatigue, infusion-related reactions, and cough in those on ofatumumab.

In all, 4% of patients on ibrutinib and 5% on ofatumumab discontinued the assigned drug because of adverse events.

Richter’s transformation – CLL evolving into an aggressive, rapidly growing large-cell lymphoma – occurred in two patients in each treatment arm. One patient on ibrutinib developed prolymphocytic leukemia.

Dr. Byrd noted that the improved PFS, overall survival, and response rates with ibrutinib were seem across all patient subgroups, including patients who were resistant to chemoimmunotherapy and those with the notorious chromosome 17p13.1 deletion.

Ibrutinib is currently being explored in patients with previously untreated CLL or SLL. The study was supported by Pharmacyclics. Dr. Byrd disclosed receiving research funding and serving as an unpaid advisor to the company. Dr. Odenike and Dr. Masters reported having no relevant disclosures.