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CLL: BTK Inhibitor Ibrutinib Promising for First-Line Treatment of Older Patients

Carlson, Robert H.

doi: 10.1097/01.COT.0000415893.08749.65

CHICAGO—Bruton's tyrosine kinase (BTK)-inhibitor ibrutinib shows “impressive” results in chronic lymphocytic leukemia, according to data presented here at the ASCO Annual Meeting (Abstract 6507). In an interview before the meeting, after the abstracts were released, John Byrd, MD, Director of the Hematologic Malignancies Program at Ohio State University James Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute, called ibrutinib “one of the most active drugs we have seen in CLL.”

“The durability of responses puts it on the radar for a potentially paradigm-shifting approach to CLL,” he said.

Ibrutinib (previously called PCI-32765) appears to work well in patients in the unfavorable group who have increased B-cell receptor signaling, he explained. This is seen with other targeted therapies such as Burkitt's lymphoma, where with treatment, an unfavorable group can be changed to a favorable group.

At the ASCO meeting, Byrd presented data on a Phase Ib/II study, which included only symptomatic, previously untreated CLL patients over age 65.

The high response rate in this challenging population, with marrow clearance and a very low progressive disease rate, suggests that single-agent ibrutinib warrants further study as a first-line treatment approach in elderly patients, Byrd and his coauthors concluded.

He noted that in the case of CLL, ibrutinib—an oral, selective, irreversible inhibitor of BTK that inhibits CLL cell proliferation, migration, and adhesion—may be a possible replacement for fludarabine-based therapy, which carries a significant risk of morbidity and mortality in the elderly.

This study evaluated two doses of single-agent ibrutinib in previously untreated patients with CLL or small cell lymphocytic leukemia (SLL). Eligible patients age 65 or older with active CLL requiring therapy by International Workshop CLL (IWCLL) guidelines received oral ibrutinib at doses of 420 or 840 mg administered daily for 28-day cycles until disease progression.

The patients' median age was 71, and 74 percent were older than 70. Response was evaluated according to 2008 IWCLL criteria. Of the 31 patients enrolled, 26 received the 420-mg dose and five, the 840-mg dose.

The 840-mg dose, though, Byrd noted, was terminated after it became evident that the activity and safety data were the same as in the lower dose in relapsed/refractory patients.

Nineteen of the 31 patients (61%) had baseline cytopenias (hemoglobin levels less than 11g/dl or a platelet count less than 100,000, and unmutated immunoglobulin heavy chain variable genes (IgVH) were present in 43 percent of patients.

He said the majority of adverse events have been Grade 2 or less in severity—most commonly diarrhea, nausea, and fatigue. Non-hematological adverse events greater than Grade 3 potentially related to ibrutinib were seen in 19 percent of patients, and 10 percent of patients had Grade 3 or higher infections or cytopenias.

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Estimated 12-Month PFS: 93%

With a median follow-up of 10.7 months, 73 percent (19 of 26 patients) in the 420-mg cohort achieved a response by IWCLL criteria, with 65 percent partial responses and 8 percent complete remissions, with no morphologic evidence of CLL on marrow, the researchers reported.

An additional 12 percent of patients (3/26) had nodal responses with lymphocytosis.

Median follow-up in the 840-mg cohort was 4.6 months, at which time two out of five achieved a partial response and one patient had a nodal response.

A total of 84 percent of patients remain on study, Byrd said. The reasons for discontinuation were adverse events in three patients and “investigator decision” for one patient. None of the patients died, and there was no disease progression, although in one patient, disease transformed to a more aggressive lymphoma, Richter's transformation, which Byrd said occurs in about three percent of CLL patients.

Most important, he said, the estimated 12-month median progression-free survival for the 420-mg cohort of patients is 93 percent, which he said compares with the one-year progression-free survival rate in an untreated best-patient population of 60 to 65 percent.

“Responses were good even in patients with genetic risk factors such as IGBH mutational status or deletion 17P.”

And the progression-free survival and response rates updated at the ASCO meeting will look even better, he said in the pre-meeting interview. “The responses to ibrutinib have been like wine—as they mature they get better.”

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Kanti Rai: ‘Welcome News’

Asked for his opinion for this article, Kanti Rai, MD, Chief of the CLL Research & Treatment Program at North Shore-Long Island Jewish Medical Center (NY), called the report by Byrd and colleagues “welcome news”—“We all have been hoping that this new drug will soon be tested in front-line therapy in CLL.”

Among his other achievements, Rai, who received the David A. Karnofsky Memorial Award at the ASCO meeting in recognition of his outstanding achievements in cancer research and for his influence on the treatment of cancer patients, established the Rai clinical staging system for CLL, which is based on an analysis of how the body is affected by the abnormal lymphocytes.

He explained that ibrutinib had first attracted attention in 2010 with a report at the American Society of Hematology Annual Meeting by Jan A. Burger, MD, PhD, and colleagues, showing remarkable efficacy in previously treated patients with CLL who had relapsed and refractory disease.

Those responses seen were especially noteworthy, Rai said, because they showed drastically shrinking, bulky, enlarged lymph nodes with acceptable levels of toxicities.

The study by Byrd et al, he said, is commendable because, “it finally pays attention to the group of CLL patients who are most representative of this disease”—i.e., elderly patients age 65 and over.

“Most of the previous therapy trials in this disease excluded the elderly, while fully recognizing that CLL is a disease of the elderly,” Rai said. “This is true even for our most popular currently used front-line regimen, FCR [fludarabine, cyclophosphamide, rituximab].”

He acknowledged that lately there have been some interesting and promising results from front-line trials in Italy and the UK in which rituximab plus oral chlorambucil have shown satisfactory activity in elderly patients who had the usual co-morbidities that accompany this age group.

He said this BTK-inhibitor's mechanism of action, resulting in lymphocytes pouring out from the enlarged lymph nodes into the peripheral circulation, might not be enough or adequate therapy if it is continued to be tested as a single agent.

“It is my hope that with these positive and promising initial Phase Ib/II results using ibrutinib as a single agent, the investigators will now rapidly move into combining this drug with an anti-CD 20 monoclonal antibody and/or any chemotherapy drug appropriate for the elderly age group,” Rai said.

Copyright © 2012 Wolters Kluwer Health, Inc. All rights reserved.
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