New investigational agent highly active in CLL patients
Ibrutinib is the first drug designed to target Bruton's tyrosine kinase
- Date : 13 Dec 2012
- Topic : Haematologic malignancies
Ibrutinib, promotes high response rate, durable remissions, and is tolerable in treatment naive and relapsed or refractory chronic lymphocytic leukaemia
Updated results from a phase Ib/II clinical trial indicates that a novel therapeutic agent for chronic lymphocytic leukaemia (CLL) is highly active and well tolerated in patients who have relapsed and are resistant to other therapy. Ibrutinib (PCI-32765) is the first drug designed to target Bruton's tyrosine kinase (BTK), a protein essential for CLL-cell survival and proliferation. CLL is the most common form of leukaemia.
Study co-leader Dr John Byrd, director of the division of haematology at Ohio State University Comprehensive Cancer Centre – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) presented these findings in the oral session at the 54th Annual Meeting of the American Society of Haematology (ASH) in Atlanta (USA), December 8-11.
The study found that response to therapy was high across cohorts, with 71% of previously untreated older patients experiencing a complete or partial response at either treatment dose (420mg and 840mg). The same response was observed in 67% of the relapsed patients and half (50%) of the high-risk patient cohort. After 22 months of follow-up, the disease had not progressed in 96% of previously untreated patients and 76% of relapsed and high-risk patients.
These findings demonstrate ibrutinib's potential as a highly active, well-tolerated first-line therapy for CLL that produces a high rate of durable remissions. The drug is effective in part because patients are willing to stay on treatment since the side effects are very tolerable, according to Dr Byrd.
Only non-severe side effects, including diarrhoea, fatigue, chest infection, rash, nausea, joint pain and infrequent and transient low blood counts were observed. Investigators found no evidence of cumulative toxicity or long-term safety concerns with a median follow-up of 16 months for treated patients.
A total of 116 CLL patients were enrolled in the study in a series of treatment cohorts, which included patients who were never treated (treatment-naive); those who had received two or more prior therapies (relapsed/refractory); those who had relapsed within two years of treatment (high-risk); and those over age 65. Two oral dosing regimens (420 mg or 840 mg) of ibrutinib were used daily. The primary goal of the study was to determine the safety of the low and high doses. Secondary objectives included efficacy, measures of the intensity of the drug's effect in the body and the long-term safety of administering continuously until relapse.
The majority of adverse effects were diarrhoea (54%), fatigue (29%), upper respiratory tract infection (29%), rash (28%), nausea (26%) and arthralgias (25%). Haematologic toxicity ≥ Gr 3 was relatively infrequent. There was no evidence of cumulative toxicity or long-term safety concerns with a median follow-up of 16 months. Estimated 22 month progression free survival for the 85 relapsed or refractory and high-risk patients was 76% and 96% for treatment-naive patients. Estimated 22 month overall survival for the 85 relapsed or refractory patients and high-risk patients was 85% and 96% for treatment-naive patients.
Funding from Pharmacyclics, Inc., supports this clinical trial. Dr John Byrd is an unpaid consultant and member of the scientific advisory board for Pharmacyclics, Inc.
Ibrutinib in combination with rituximab is well−tolerated and displays profound activity in high-risk CLL patients
The combination of the novel investigational agent ibrutinib with an established therapeutic antibody, rituximab, may present a safer and more effective option than the current standard chemotherapy-based treatment regimen for patients with high-risk CLL.
Data from earlier studies of ibrutinib have shown it to be equally effective in both low- and high-risk CLL. High-risk CLL patients typically have unfavourable responses to standard CLL therapies and a dismal outcome. Such patients are characterized by presence of chromosomal abnormalities (e.g. deletions of chromosome 17p or 11q) or short remissions (less than 3 years) after standard chemo-immunotherapy. To develop an alternative therapy regimen for this patient population, researchers explored the combination of ibrutinib and the anti-CD20 antibody rituximab in high-risk CLL.
In this phase II study conducted at The University of Texas MD Anderson Cancer Center in Houston, ibrutinib was given in combination with rituximab to evaluate its potential to accelerate and improve CLL patient responses. Forty patients were treated with 420 mg of ibrutinib daily in combination with weekly rituximab for four weeks, followed by ibrutinib daily plus monthly rituximab until month six, followed by single-agent ibrutinib.
Positive responses to therapy were shown among the vast majority of treated patients. At four months of follow-up, the overall response rate was 85% and almost all (38 of 40) patients continued on therapy without disease progression. Of the 20 patients evaluable for early response, 17 achieved a partial remission. Patient health questionnaires also noted improvements in health and the quality of life of all treated patients.
Overall, the regimen was well-tolerated among participants, with little severe toxicity that was largely unrelated and short in duration. After treatment with ibrutinib-rituximab combination therapy, most cases of early lymphocytosis, due to the ibrutinib-induced shift of CLL cells from lymph node tissues into the blood, peaked early and resolved; at four months of follow-up, only three treated patients had lymphocytosis that had not yet resolved. This shorter lymphocytosis duration, when compared to single-agent use of ibrutinib, is presumably related to the addition of rituximab.
It is well known that high-risk CLL patients struggle with the effects of standard chemo-immunotherapy and eventually become resistant. For these patients, ibrutinib in combination with rituximab appears to be a safer option with high efficacy and without the related risks, according to Dr Jan Burger, lead author and Associate Professor of Medicine in the Department of Leukaemia at The University of Texas MD Anderson Cancer Center. Based on these promising results, larger-scale studies of ibrutinib-rituximab in high-risk CLL are needed. The study results were presented as an oral presentation at the 54th Annual Meeting of the American Society of Haematology (ASH).
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