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CLL: ‘Potent,‘ Well-Tolerated Activity for Ibrutinib, Irrespective of Deletion 17p

Carlson, Robert H.

doi: 10.1097/01.COT.0000431572.99089.4f


Figure. Ib

Figure. Ib

WASHINGTON—the BTK inhibitor ibrutinib appears to be very potent against chronic lymphocytic leukemia (CLL), with responses seen in patients irrespective of their deletion 17p mutation (del 17p) status.

In addition it is well tolerated, say researchers at the National Heart Lung and Blood Institute, who reported a high overall and extended response in patients with untreated, relapsed, and unresponsive CLL who had both peripheral blood, lymph node, and organ involvement.

Clinical and translational results of the Phase II trial of the inhibitor of B-cell receptor signaling were presented here at the American Association for Cancer Research Annual Meeting by Adrian Wiestner, MD, PhD, head of the Lymphoid Malignancies Section in the Hematology Branch, who reported an estimated progression-free survival rate of 94 percent at 12 months (Abstract LB-141).

Among 44 patients evaluable at six months, 54 percent of those with del 17p had a partial response according to the criteria of the International Workshop on Chronic Lymphocytic Leukemia (IWCLL), as did 55 percent of a cohort of patients age 65 or older who did not have the deletion.

And, 42 percent of the del 17p group and 40 percent of the non-deletion, older group had partial responses in nodal disease although the patients continued to have lymphocytosis.

Wiestner noted that many elderly patients with CLL are unable to tolerate current aggressive standard therapies, and those with del 17p have particularly poor outcomes with chemotherapy.

All participants in the trial had decreased splenomegaly, with a median reduction in volume of 55 percent, he reported. Tumor infiltration fell by a median of 82 percent in the 26 patients who had a bone marrow biopsy, while the absolute lymphocyte count decreased by a median of 62 percent. “There was a dramatic reduction in lymphadenopathy in almost all patients,” Wiestner said.

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Breakthrough Therapy Designation

Ibrutinib is a selective inhibitor of Bruton's tyrosine kinase, a component of the B-cell receptor signaling pathway that plays a key role in the development and progression of CLL. It currently has no label indications, but in April was granted a U.S. Food and Drug Administration “breakthrough therapy” designation for CLL and small lymphocytic lymphoma with del 17p, which followed another such designation two months earlier for use in patients with relapsed or refractory mantle cell lymphoma or Waldenstrom's macroglobulinemia (OT, 3/25/13 issue). Ibrutinib trials in these cancers are ongoing.

Patients in the trial received oral ibrutinib at 420 mg daily, and adverse events effects were generally mild, Wiestner said.

Adverse events included Grade 1/2 diarrhea, fatigue, arthralgia, mouth sores, cramps, and rash. Grade 3 rash and infections that led to dose reductions were seen in 13 percent of patients.

There were two deaths among the patients in the study, which Wiestner said were presumed due to infections and not ibrutinib treatment, occurring at day three of therapy and at seven months afterward.

“This study confirms the single-agent antileukemia activity seen in prior Phase I/II studies and extends this experience, particularly in deletion 17p CLL,” he concluded.

The study was supported by the NHLBI Intramural Research Program, with the product provided by the drug's manufacturer, Pharmacyclics, Inc.

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Impact on Functional Activity in CLL Pathway

Over the years several of the effective treatments for CLL that have been developed, perhaps the most established and effective is the FCR regimen of fludarabine, cyclophosphamide, and rituximab, noted the moderator of the session at which the ibrutinib results were reported, Kenneth Anderson, MD, Director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute, speaking in an interview after the session.

FCR, however, is less effective in del 17p CLL patients, he said.

“The novelty of ibrutinib as a targeted therapy is that it impacts the functional activity of the pathway that mediates proliferation of CLL, and it hits that pathway in the CLL cell very effectively.”

Asked whether any of the other kinases targeted by ibrutinib are implicated in CLL, Anderson said probably not. “But conversely, BTK is implicated in the normal maturation and function of osteoclasts, so correlative science studies should potentially examine that in bone disease.”

Another exciting CLL treatment is lenalidomide, he added, noting, though, that he thought the most promising and furthest along in terms of clinical testing are ibrutinib and the protein kinase C (PKC) 110 Delta inhibitor.

“But the BTK inhibitor is, I think, one of the most exciting drugs to come along in B-cell lymphoma in over a decade—it's very good,” he said.

© 2013 Lippincott Williams & Wilkins, Inc.
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