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news.Pharmacyclics, announced that treatment with single-agent IMBRUVICA (ibrutinib) in treatment-naive and previously treated patients with chronic lymphocytic leukemia (CLL) resulted in a significant response rate, with 92% of high-risk CLL patients with deletion 17p (del 17p) or tumor protein 53 (TP53 aberrations) achieving an objective response.
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These high-risk patients typically do not respond well to standard therapies. These results were published in The Lancet Oncology. IMBRUVICA is jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.
"Ibrutinib treatment results observed in CLL patients with del 17p or TP53 aberrations are very encouraging given that these patients have a high relapse rate after chemotherapy and are in need of tolerable, effective, and durable treatment options," said Mohammed Farooqui*, D.O., Staff Clinician, Laboratory of Lymphoid Malignancies, National Heart, Lung, and Blood Institute and lead author of the publication.
When functioning normally, the TP53 gene produces a protein called p53, which acts as a tumor suppressor and regulates cell division by preventing cells from growing and dividing too quickly. If TP53 is damaged or a copy of the gene is lost, it can result in aberrations which cause cells to grow in an uncontrolled way, resulting in early disease relapse and poor survival rates.
In addition, CLL patients with deletion of the short arm of chromosome 17 are considered to have the poorest prognosis.4 These mutations often occur together and are present in approximately 7-11.5% of treatment-naive CLL patients.2,5,6
"This study is important as it is the largest prospective cohort of del 17p CLL patients treated with single-agent IMBRUVICA as first-line therapy," said Danelle James, M.D., M.S., Vice President, Clinical Development, Pharmacyclics.
"These positive IMBRUVICA results are very exciting and reinforce the effectiveness and tolerability of IMBRUVICA in patients with del 17p CLL, while demonstrating its potential utility in earlier lines of treatment for this difficult-to-treat, high-risk group of CLL patients."
The Phase II, open-label, single-center study enrolled 51 CLL patients at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD. Thirty-five patients had previously untreated disease and 16 patients had relapsed or refractory CLL.
The primary endpoint of the study was overall response rate (ORR) after 24 weeks, and secondary endpoints included safety, overall survival, progression-free survival (PFS), best response and nodal response. Forty-seven of the 51 patients (92%) enrolled in this study had del 17p CLL and four patients carried the TP53 aberration but did not have the del 17p mutation.
At the time of analysis, the median follow-up for all patients was 24 months (15 months for the previously untreated cohort). At 24 weeks, 48 patients were evaluable for response, assessed according to the modified International Workshop on Chronic Lymphocytic Leukemia 2008 criteria.
Ninety-two percent (n=44) of patients achieved an objective response (95% CI, 84-100), 50% achieved a partial response (PR; n=24) and 42% achieved a PR with lymphocytosis (n=20). The ORR rate and depth of responses increased over time.
The estimated PFS at 24 months for all patients on an intention-to-treat basis was 82% (95% CI, 71-94). Forty-two of the 51 patients enrolled in the study (82%) continued on IMBRUVICA treatment without disease progression.
After eight weeks on therapy, IMBRUVICA was associated with a > 50% mean reduction in tumor burden in the bone marrow (44%), lymph nodes (70%) and spleen (79%) in patients. After 24 weeks of therapy, the rates of tumor burden reduction ( > 50%) increased to 83%, 93% and 95%, respectively.
Most non-hematologic adverse events were Grade 1 or 2. The most common adverse events (AEs; occurring in > 30% of all patients) potentially related to IMBRUVICA treatment were arthralgia (59%), diarrhea (51%), rash (47%), nail ridging (43%), bruising (33%) and muscle spasms (31%).
The most common nonhematologic Grade 3 adverse event was pneumonia in three patients (6%). No bleeding events > Grade 3 occurred. The most frequent Grade 3 or 4 hematologic AEs in this study were neutropenia (24%), anemia (14%) and thrombocytopenia (10%). Nine patients (18%) discontinued treatment; reasons for discontinuation included disease progression in five patients (10%) and three deaths (6%).