Friday, 8 January 2016
Ibrutinib can be used in CLL who have developed P17 deletion also
The Bruton’s tyrosine kinase inhibitor ibrutinib was compared with the alkylating agent chlorambucil in patients with chronic lymphocytic leukemia.In a new Original Article, ibrutinib was associated with a higher response rate, longer duration of response, and longer overall survival.
Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in Western countries; it affects primarily older persons, with a median age at diagnosis of 72 years. Chlorambucil has been a standard first-line therapy in CLL, especially for older patients or those with coexisting conditions. Until recently, no treatment was clearly superior to chlorambucil in this population. Findings from multiple recent studies suggest a role for single-agent ibrutinib as initial treatment in patients with CLL. Burger et al. conducted a multicenter, open-label, randomized phase 3 trial to evaluate the efficacy and safety of single-agent ibrutinib as compared with chlorambucil in patients 65 years of age or older with previously untreated CLL.
• What are some of the limitations of current first-line therapies for CLL?
All current standards for first-line CLL therapy are based on cytotoxic chemotherapy, including alkylating agents, purine analogues, or combinations thereof, except for patients with chromosome 17p13.1 deletion, for whom ibrutinib is a primary consideration for first-line therapy according to consensus guidelines. In addition to their myelosuppressive effects, these cytotoxic chemotherapy approaches may be associated with expansion of subclones with high-risk genetic abnormalities (e.g., TP53 or NOTCH1 mutation) and an increased risk of secondary cancers, including treatment-related myelodysplasia and acute myeloid leukemia.
• Is progression-free survival prolonged with the use of ibrutinib as compared to chlorambucil in patients 65 years of age or older with previously untreated CLL?
In the study by Burger et al., ibrutinib resulted in significantly longer progression-free survival than that with chlorambucil (median, not reached vs. 18.9 months) as assessed by the independent review committee, with a relative risk of progression or death that was 84% lower than that with chlorambucil (hazard ratio, 0.16; 95% confidence interval [CI], 0.09 to 0.28; P<0.001). The rate of progression-free survival at 18 months was 90% in the ibrutinib group versus 52% in the chlorambucil group. The results of the analysis of progression-free survival were consistent in the higher-risk subgroups, including patients with advanced-stage cancer, higher ECOG performance-status score, presence of chromosome 11q22.3 deletion, and nonmutated IGHV status.
Q: How do overall survival and response rates compare among patients 65 years of age or older with previously untreated CLL who receive ibrutinib as compared to chlorambucil?
A: In the study by Burger et al., ibrutinib significantly prolonged overall survival (median, not reached in either group). The overall survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death with ibrutinib that was 84% lower than that with chlorambucil (hazard ratio, 0.16; 95% CI, 0.05 to 0.56; P=0.001). The response rate as assessed by the independent review committee was significantly higher in the ibrutinib group than in the chlorambucil group (86% vs. 35%). Furthermore, ibrutinib-treated patients had a restoration of bone marrow function, with a significantly higher rate of sustained improvement in hematologic variables.
Q: What adverse events were associated with ibrutinib in the Burger study?
A: The safety of ibrutinib in this older population of patients with CLL who often had clinically significant coexisting conditions was consistent with that in previous reports. Exposure to treatment and adverse-event follow-up was nearly 2.5 times as long with ibrutinib as with chlorambucil. In the ibrutinib group, diarrhea was the most frequent adverse event (in 42% of the patients, including grade 3 diarrhea in 4%). Other adverse events that occurred in 20% of the patients in the ibrutinib group were fatigue, nausea, and cough. Similar to findings in previous reports about ibrutinib, major hemorrhage was observed in 4% of the patients, with no fatal events, and atrial fibrillation occurred in 6%, with the majority of the events (in six of eight patients) being grade 2 events that were observed over the period of 1.5 years while the patients were taking ibrutinib. Hypertension was reported more frequently with ibrutinib than with chlorambucil, with no events leading to dose modification or having a severity of grade 4 or 5. The rates of fatigue, nausea, vomiting, and myelosuppression were higher with chlorambucil than with ibrutinib. Early discontinuation of treatment owing to adverse events was more than twice as frequent with chlorambucil as with ibrutinib
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