Philip L. McCarthy, MD
Several trials of ibrutinib, an oral kinase inhibitor, either alone or in combination with currently used therapies for patients with chronic lymphocytic leukemia (CLL) were presented at the 55th Annual Meeting of the American Society of Hematology.
Ibrutinib (Imbruvica), which is marketed by California-based Pharmacyclics, was recently approved as a monotherapy for patients with mantle cell lymphoma who have received at least one prior therapy. The oral drug received a Breakthrough Therapy Designation from the FDA in April 2013 for particularly poor prognosis and high-risk CLL or small lymphocytic lymphoma (SLL) patients who carry a deletion in chromosome 17 (17p deletion). CLL patients who harbor the 17p deletion generally have poor outcomes when treated with standard chemotherapy and immunotherapy regimens.
Ibrutinib specifically inhibits the Bruton’s tyrosine kinase (BTK), a crucial component of both normal and malignant B-cell receptor signaling that has been shown to modulate the tumor microenvironment and promote survival and growth of CLL. Thus far, the drug has demonstrated less toxicity for patients compared with standard treatment regimens.
In the phase Ib/II PCYC-1102 monotherapy study in relapsed, refractory CLL (N = 85), patients who received 420 mg of ibrutinib daily had an overall response rate (ORR) of 71% (N Engl J Med
. 2013;369:32-42). The estimated progression-free survival (PFS) rate at 26 months was 75%.
“This is one of several compounds that are targeting specific pathways in the CLL cell that will likely lead to long-term control and possibly cure of this disease,” said Philip L. McCarthy, MD, of the Blood and Marrow Transplant Program at the Roswell Park Cancer Institute in Buffalo, New York.
Activity in Combination with Bendamustine and Rituximab
Combining ibrutinib with the chemoimmunotherapy regimen of bendamustine (Treanda) plus rituximab (Rituxan) demonstrated a high level of activity and was tolerable for patients with relapsed or refractory CLL.1
Presenting the final results of the 30-patient study, Jennifer Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute in Boston, Massachusetts, said those patients with a molecular marker of high-risk disease and those with bulky disease were as likely to respond as all patients on the trial.
Jennifer R. Brown, MD, PhD
The ORR was 93.4% (28/30) including five complete responses and three nodal partial responses, with no differences in responses based on risk features such as a 17p deletion. An additional patient had a partial response with lymphocytosis (PRL). The estimated PFS at 12 months was 90% but the median PFS has not yet been reached.
“Although it is difficult to compare studies, these results suggest that these responses are higher than those seen in previous phase II studies of bendamustine plus rituximab alone,” said Brown.
Twenty-one of the patients are continuing on an ibrutinib extension study and 18 are still on treatment about 12 months later with no evidence of progression, Brown said during her presentation. Nine patients have discontinued, with five going on to a stem cell transplant and four with disease progression.
“This is a very nice study with good outcomes in these [previously treated patients]. It will be important to see how long these responses are maintained,” said McCarthy, who was not involved in the study.
The median age of patients on the trial was 62. Patients had a median of two prior therapies and 13% had three or more prior therapies. The median treatment follow-up was 16 months. Twenty-three percent of patients had a 17p deletion and 43% had an 11q deletion.
Patients tolerated the three-drug regimen relatively well: the median number of completed cycles was the full six. No patients have discontinued the drug due to adverse events (AEs) and no deaths were reported on the study.
The most frequent treatment-related AEs were diarrhea (70%), nausea (66.7%), fatigue (46.7%), neutropenia (40%), and upper respiratory tract infection (36.7%). Grade ≥3 AEs included neutropenia (40%), maculopapular rash (10%), and fatigue (10%), as well as cellulitis, thrombocytopenia, and febrile neutropenia (6.7% each).