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 2013 ASH annual meeting.
On February 12, the FDA announced an expansion of its approval of ibrutinib to include the treatment of patients with CLL who have received at least one previous therapy. Ibrutinib was previously approved as a monotherapy for patients with mantle cell lymphoma who have received at least one prior therapy.
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. The drug has shown less toxicity for patients compared with standard 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.
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.
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.
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).
The combination resulted in profound activity in high-risk CLL patients and was well tolerated, said Jan Burger, MD, PhD, associate professor of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, who presented the results. “The addition of rituximab clearly accelerates responses in CLL,” said Burger. “But the question is whether this response will translate into substantial benefit for patients in the long run. That is what we are currently testing.”
The combination also improved the quality of life of patients. In self-reported quality-of-life questionnaires, the proportion of patients reporting high quality of life increased from 46% prior to treatment to 89% after 6 months of ibrutinib therapy.
At a median follow-up of 14 months, 31 of the 40 patients are still on treatment (including 16 of 20 patients with a 17p deletion or TP53 mutation) with no disease progression. The estimated overall survival at 18 months is 84%.
Several patients had infection complications including six patients with pneumonia and three upper respiratory infections. Low-grade adverse events included bruising, subdural hematoma, fatigue, bone pain, and arthralgia.
The combination is currently being tested in an ongoing phase III, randomized, 150-patient clinical trial (NCT01973387).
Chronic lymphocytic leukemia (CLL) is the most common type of cancer in older adults. Recently during the Annual Meeting of the American Society of Hematology, it was noted that the oral kinase inhibitor ibrutinib, used either alone or in combination with currently FDA-approved therapies, showed overall response rates better than anticipated while improving quality of life.
Currently, we have chemotherapies that have shown great response rates, yet without a cure for CLL patients. Ibrutinib being utilized in combination modality with bendamustine and rituximab showed an overall response rate of 93.4% which we have not seen in a long time. When reviewing the results, one must be careful in understanding the breakdown of different grades of adverse events that may have occurred when utilizing combination therapy. In this case, precautions to prevent infection, diarrhea, nausea, fatigue, neutropenia, and rash should be taken early or preventive measures should be in place.
It is very exciting to have an oral agent such as ibrutinib used as a mono or combination therapy. As a healthcare professional, I try to make sure a thorough analysis of the patient history is undertaken before prescribing any chemotherapy in order to avoid adverse events.