Treatment for chronic lymphocytic leukemia (CLL) has resulted in few cases of durable remissions. Bruton’s tyrosine kinase (BTK), an essential component of B-cell receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells. Ibrutinib, an oral covalent inhibitor of BTK designed for the treatment of B-cell cancers, has shown that treatment with this drug inhibits numerous processes. Ibrutinib also does not have toxic effects on normal T-cells. A new study investigated the safety and efficacy of 2 different ibrutinib doses in patients with relapsed or refractory disease (Byrd JC, et al. N Engl J Med. 2013;369:32-42).
In this phase 1b-2, open-label, multicenter study, 85 patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) were randomized to receive 420 mg of ibrutinib (N = 51) or 840 mg of ibrutinib (N = 34). Both doses were administered orally on a continuous schedule until the onset of disease progression or unacceptable toxicity. A majority of these patients had high-risk disease and had received a median of 4 previous therapies. At a median follow-up of 20.9 months, 64% were still receiving treatment and 36% had discontinued treatment.
Long-term therapy with ibrutinib was associated with modest toxicity; most adverse events were grade 1 or 2. The most common adverse events included transient diarrhea (47%), upper respiratory tract infection (33%), and fatigue (28%); a majority of adverse events resolved without the need for treatment suspension. The overall response rate was 71% for both treatment arms, and an additional 20% in the 420-mg group and 15% in the 840-mg group experienced a partial response with lymphocytosis.
The response was independent of clinical and genomic risk factors present before treatment. After a follow-up of 26 months, the estimated rate of progression-free survival was 75%, and the rate of overall survival was 83% for all patients, irrespective of the dose.
These results suggest that monotherapy with ibrutinib is associated with an increased frequency of durable disease remission in patients with relapsed and refractory CLL and SLL, including patients with high-risk genetic disease.
It is noteworthy that this study, which was initially designed with 2 arms, was expanded to include a third arm of patients with high-risk disease. Complete or partial responses increased over time and peaked at 18 months of therapy. The drug was rapidly absorbed and blocked the BTK enzyme almost completely (a reflection of surrogate kinase inhibition). Ibrutinib is still not available commercially, but this study may provide enough data to allow for its approval as an orphan drug.
