CHICAGO – Ibrutinib continues showing strength in a large majority of patients with chronic lymphocytic leukemia, including those with poor-prognosis chromosomal deletions, a study showed.

Three-year follow-up data of patients treated with ibrutinib (Imbruvica) monotherapy in a phase II trial and extension study showed 30-month overall survival (OS) rates of 96.6% for patients who received ibrutinib after an initial diagnosis, and 79.9% for patients with relapsed or refractory disease. Median overall survival has not been reached for either group, reported Dr. Susan M. O’Brien of the University of Texas M.D. Anderson Cancer Center, Houston.

Among patients with the poor-prognosis chromosome 17p deletion (del17p), 30-month OS was 65.9%, with the median OS not yet reached, Dr. O’Brien reported at the annual meeting of the American Society of Clinical Oncology.

"We achieved very rapid and quite durable responses with single-agent ibrutinib. We have not reached a median duration of response," she said.

The best investigator-assessed responses were 87% among 31 treatment-naive patients, and 90% among those with relapsed/refractory disease, some of whom had received four prior lines of therapy.

"I think one example of how this data will change clinical practice was the progression-free survival based on cytogenetics," commented invited discussant Dr. Nicole Lamanna of Columbia University Medical Center, New York.

The 30-month progression-free survival (PFS) by cytogenetics (as determined by fluorescence in situ hybridization) was 45.9% for patients with del17p, 74.2% for patients with the 11q deletion (del11q), and 89.0% for patients with neither deletion. The median PFS was 28.1 months among patients with del17p, but has not been reached in patients in the other two cytogenetic groups.

"With some of the other regimens that have been presented in patients with 17p, clearly a median PFS of this length has really not been achieved," she said.

In a separate study, also presented at ASCO 2014, investigators reported the results of the first interim analysis of a phase III randomized trial, which showed that 1-year overall survival for patients with previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) assigned to receive ibrutinib was 90%, compared with 81% for patients assigned to ofatumumab (Arzerra).

Independent Review

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.

Dr. O’Brien and colleagues reviewed data on 31 patients aged 65 and over with newly diagnosed, untreated CLL/SLL, and 101 patients with relapsed/refractory CLL/SLL. The relapsed/refractory group included patients with high-risk CLL/SLL, defined as disease progression within 24 months of starting a chemoimmunotherapy regimen, or as a failure to respond.

The investigators initially tested ibrutinib at 420 and 840 mg daily doses, but soon discovered that there were no differences in efficacy or toxicity between the two doses. Dr. O’Brien therefore reported combined data on patients treated at each dose level.

For patients with relapsed/refractory disease, the median number of prior therapies was 4 (range, 1-12). All patients in this group had received chemotherapy, and more than 90% had received a nucleoside analogue, an alkylating agent, and anti–CD20-based therapy.

In all, 6% of treatment-naive patients and 34% of relapsed/refractory patients had del17p. Del11q was seen in 3% and 35% of patients, respectively.

At the most recent analysis, 25 of 31 treatment-naive patients (81%) and 42% of relapsed/refractory patients had been on ibrutinib for 2-3 years. Only one patient in the treatment-naive group and 19 in the relapsed/refractory group discontinued therapy because of disease progression.

Of the treatment-naive patients with responses, 13% had a complete response (CR), 3% had a near CR, 65% had a partial response (PR), and 6% had a PR with lymphocytosis. Of the relapsed/refractory group, 6% had a CR, 80% had a PR, and 4% had a PR with lymphocytosis.

The responses tend to improve over time, with a median time to first response of 1.9 months, and a median time to best response of 7.3 months.

Adverse events of grade 3 or greater occurred in 19 treatment-naive patients and 83 relapsed/refractory patients. Of these events, 7 (23%) in treatment-naive patients and 32 (32%) in relapsed/refractory patients were deemed to be ibrutinib related. One patient in the treatment-naive group and 11 in the relapsed/refractory group died during the study.

"If we look now at the adverse events over time, we see that in fact they tend to go down, and so – this is important – we’re not seeing a late, surprising side effect with 2 or 3 years of follow-up in terms of things that we didn’t see when we first started the patient on study," Dr. O’Brien said.

The most common side effects were hypertension and pneumonia.

The PCYC-1002 and -1003 studies were supported by Pharmacyclics. Dr. O’Brien disclosed receiving research funding from the company. Dr. Lamanna disclosed consulting/advising for Celgene, and receiving research funding from several companies, but not Pharmacyclics.

Ibrutinib holds CLL at bay in majority of patients at 30 months