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Ibrutinib shows promise for advanced CLL with 17p deletion
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Ibrutinib induced a high overall response rate and demonstrated a favorable safety profile in patients with relapsed or refractory chronic lymphocytic leukemia with 17p deletion, according to results of an open-label, phase 2 study.
“The p53 tumor suppressor protein plays a crucial role in oncogenesis and response to chemotherapy in human cancers,” Susan O’Brien, MD, professor in the division of hematology and oncology at UC Irvine Health and director of the Sue and Ralph Stern Center for Cancer Clinical Trials and Research, and colleagues wrote. “The TP53 gene is found on the short arm of chromosome 17 (17p) and is deleted or mutated in over 50% of malignancies. Historically, patients with CLL with 17p deletion have a poor prognosis with diminished OS and inferior clinical outcomes compared with those without 17p deletion when treated with chemotherapy and chemoimmunotherapy-based regimens.”
O’Brien and colleagues sought to determine the safety and efficacy of the oral tyrosine kinase inhibitor ibrutinib (Imbruvica; Janssen, Pharmacyclics) in patients with relapsed or refractory CLL or small lymphocytic lymphoma with 17p deletion.
The analysis included 144 patients (median age, 64 years; interquartile range [IQR], 57-72; median prior treatment lines, n = 2) assigned 420 mg daily oral ibrutinib until disease progression or unacceptable toxicity.
Overall response rate served as the primary outcome measure. Planned exploratory analyses investigated PFS, OS, sustained hematological improvement and immunological improvement.
The study remains ongoing; median follow-up at the preplanned primary analysis was 11.5 months (IQR, 11.1-13.8).
At the interim analysis, 92 patients achieved an independently confirmed response, for an ORR of 64% (95% CI, 56-71). The investigator-assessed ORR was 82% (95% CI, 76-88; n = 119).
Researchers conducted an extended analysis after a median follow-up of 27.6 months (95% CI, 14.6-27.7). By this time, there were 12 complete responses, three complete responses with incomplete bone marrow recovery, and 92 partial responses. The investigator-assessed ORR in this analysis was 83% (95% CI, 76-89; n = 120).
The rate of 24-month PFS was 63% (95% CI, 54-70) and 24-month OS was 75% (95% CI, 67-81). Ninety-one patients had any baseline cytopenia, of whom 79% (n = 72) achieved a sustained hematological improvement.
The researchers did not observe clinically significant changes from baseline to 24 months in immunoglobulin A (0.4 g/L vs. 0.7 g/L), immunoglobulin G (5 g/L vs. 4.9 g/L) or immunoglobulin M (0.3 g/L for both).
Fifty percent of the patient population (n = 72) discontinued treatment due to progressive disease (n = 34), unacceptable toxicity or death (n = 24), consent withdrawal (n = 9) or investigator decision (n = 5).
Thirteen patients experienced major bleeding, 11 cases of which were grade 3 or grade 4; however, no bleeding episodes resulted in death.
Grade 3 or grade 4 infections occurred in 43 patients. Nineteen patients experienced grade 3 or worse pneumonia.
Thirty-eight patients died during the extended analysis, 18 of which were due to adverse events. Fatal adverse events occurring in more than one patient included pneumonia (n = 4), CLL (n = 3), Richter syndrome (n = 2) and sepsis (n = 2).
One patient each died of acute myocardial infarction, septic shock, encephalopathy, general physical deterioration, abnormal hepatic function, MI and renal infarction.
“Alongside data from other emerging treatments, ibrutinib might contribute to a reassessment of the role and timing of stem cell transplantation by changing the choice and sequence of treatments used for management of high-risk CLL,” O’Brien and colleagues wrote. “These data mark an era of targeted therapeutics that is changing historical treatment algorithms for patients with CLL or small lymphocytic lymphoma with 17p deletion, the most difficult subset of patients to treat.”
Although these findings advance research, they are unlikely to change current practice, Paolo Ghia, MD, PhD, of the division of experimental oncology at IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele in Milan, Italy, wrote in a related editorial.
“We can probably conclude that this work will not lead to a practice change in the treatment of patients with high-risk CLL for the simple reason that, for the sake of our patients, practice has already changed recently,” Ghia wrote. “However, it reassures us that the activity of ibrutinib in patients with CLL with 17p deletion is not just an impression obtained from a handful of patients, but is now supported by more robust data. The efficacy shown in O’Brien and colleagues’ study is another step toward solving the puzzle of how to treat patients with abnormalities in the TP53 gene, and combinations of newly identified effective drugs will be the future treatment of high-risk patients with CLL.” – by Cameron Kelsall
Disclosure: Pharmacyclics funded this study. O’Brien reports research funding and honoraria from, as well as consultant roles with, Janssen and Pharmacyclics. Please see the full study for a list of all other researchers’ relevant financial disclosures. Ghia reports grants or personal fees from AbbVie, Adaptive Biotechnologies, Celgene, Gilead, GlaxoSmithKline, Janssen, Pharmacyclics and Roche.
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