Early findings from the phase III RESONATE study, presented at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO), being held May 30 – June 3, 2014 in Chicago, Ill, indicates that ibrutinib (Imbruvica?; Pharmacyclics/Janssen Biotech), an anticancer drug targeting B-cell malignancies approved by the U.S. Food and Drug Administration (FDA) in November 2013 for the treatment of mantle cell lymphoma and in February 2014, through the 
FDA?s accelerated review process, less than five years after entering phase I clinical trials, for the treatment of chronic lymphocytic leukemia (CLL), yields lasting tumor responses and marked improvement in survival over standard ofatumumab for patients with relapsed CLL. [1]
This is the first time an oral drug has demonstrated a survival improvement over standard therapy in relapsed CLL. Just as important, the therapy was well tolerated by patients, causing only few serious side effects.
These results provide a compelling new treatment option for patients with chronic lymphocytic leukemia, including older adults with this disease, and will significantly change practice…
Leukemia in adults
CLL is the most common form of leukemia in adults. Based on data from the American Cancer Society, the estimated number of new cases of chronic lymphocytic leukemia (CLL) is 15,720 in 2014 in the United States. There are 4,600 deaths expected from the disease in the United States in 2014. The standard treatment for CLL is chemo-immunotherapy, a combination of intensive chemotherapy and an antibody such as rituximab (Rituxan?; Genentech/MabThera?; Roche). However, elderly patients, who account for the majority of patients with CLL, often cannot tolerate intensive chemotherapy. Ofatumumab (Arzerra?; GSK) is an alternative option for such patients, but studies have shown it is much less effective than intensive chemotherapy.
Significant Improvement
?With ibrutinib, about 80% of patients were still in remission at one year, twice as many as we would expect with standard therapy,? said lead study author John Byrd, MD, a professor of medicine at The Ohio State University Comprehensive Cancer Center in Columbus, Ohio.
?Although the follow-up was short in this study, the data definitely support the use of ibrutinib before anything else in this setting,? Byrd continued.
In the study, 391 patients with relapsed or refractory CLL or small lymphocytic lymphoma (a subtype of CLL) that had progressed after two or more prior therapies were randomly assigned to treatment with ofatumumab or ibrutinib. The median patient age was 67 years, and 40% were older than 70 years.
At a median follow-up of 9.4 months, the response rates were dramatically higher in the ibrutinib arm compared to the ofatumumab arm (42% vs. 4%). An additional 20% of patients treated with ibrutinib had a partial response with persistent lymphocytosis (increase in white blood cells called lymphocytes). Ibrutinib was associated with an 80% lower risk of disease progression and a 57% lower risk of dying compared to ofatumumab, the median progression-free and overall survival have not been reached. Ibrutinib had similarly high activity in two very high-risk groups of patients (17p deletions and purine analog refractory).
Early results
Based on these striking early results, patients in the ofatumumab arm were offered the opportunity to cross over to the ibrutinib arm, and patient follow-up continues. According to the researchers, the median overall survival is expected to be in the range of several years.
Well tollerated
Overall, both ibrutinib and ofatumumab were well tolerated. Diarrhea, minor bleeding, and atrial fibrillation were more common in the ibrutinib arm, whereas peripheral neuropathy was more common in the ofatumumab arm. This study alleviated concerns about kidney problems that were raised in the phase II ibrutinib study.
Commenting on the trial results, Olatoyosi Odenike, MD, ASCO Expert, Associate Professor of Medicine and an expert in the care of adults with leukemia, chronic myeloproliferative diseases, and myelodysplastic syndromes, noted: ?This phase III study in relapsed refractory chronic lymphocytic leukemia confirms that ibrutinib, administered orally, has significant efficacy and is well-tolerated. These results provide a compelling new treatment option for patients with chronic lymphocytic leukemia, including older adults with this disease, and will significantly change practice.”
For more information:
[1] Byrd JC, Brown JR, O’Brien SM, Barrientos JC, Kay NE, Reddy NM, Coutre SE, Tam C, et al. Randomized comparison of ibrutinib versus ofatumumab in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the phase III RESONATE trial. 2014 ASCO Annual Meeting. Oral Abstract Session. Tuesday June 3, 9:45 AM to 12:45 PM. Abstract No: LBA7008. Citation: J Clin Oncol 32:5s, 2014 (suppl; abstr LBA7008)[Abstract]
Photo: John C. Byrd M.D. at the American Society of Clinical Oncology Annual Meeting, May 30 – June 3, 2014. Photo Courtesy: ? ASCO/Phil McCarten.
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