CLL/SLL is an incurable disease, even with widespread use of chemoimmunotherapy, with up to one-third of patients being refractory to initial fludarabine-based therapy.12 All patients eventually relapse, so additional effective treatments are needed. Btk protein and mRNA have been shown to be overexpressed in CLL/SLL, making Btk inhibitors a logical choice for study.13 PCI-32765 has been evaluated in 61 patients with relapsed/refractory CLL or SLL that had been treated with at least two prior therapies, including fludarabine.14 This study was presented at the 2011 American Society of Hematology Annual Meeting. A poor-risk feature (del 17p, del 11q, IgVH unmutated) was present in 72% of those enrolled.
Patients were assigned to either PCI-32765 420mg daily or 840mg daily, and generally tolerated the drug well. The dose was reduced for AEs in 2 of 27 patients receiving 420mg and 4 of 34 patients receiving 840mg. Similar to the study in MCL, the most frequent AEs were grade 1 or 2 diarrhea, fatigue, and nausea. Grade 3 or higher AEs potentially related to PCI-32765 occurred in 21% of patients. The ORR by international working group criteria in the 420mg cohort was 48% at 6.2 months median follow-up and resulted in 70% at 10.2 months median follow-up. In the 840mg cohort, with 6.5 months median follow-up, the ORR was 44%. The 6-month progression-free survival is 92% in the 420mg cohort and 90% in the 840mg cohort. Based on these impressive results in patients with relapsed/refractory disease, Phase III trials of PCI-32765 are planned.
AVL-292 is an inhibitor of Btk that covalently binds to the enzyme and inhibits proliferation and activation of normal human B-cells and inhibits proliferation and survival of cells in a human lymphoma cell line.15 A Phase I study in healthy subjects found the compound to be well tolerated and capable of binding to Btk in freshly collected peripheral B lymphocytes. Btk engagement continued throughout a 24-hour time period, suggesting that once-daily dosing will be appropriate.16
Interfering with the effect of the BCR in B-cell malignancies by the use of Btk inhibitors is a promising approach. In uncontrolled trials, impressive and durable responses have been observed in patients with a range of refractory tumors. The toxicity thus far has been mild. Hematologic toxicity has been uncommon, which is an important consideration for patients who often receive many lines of myelosuppressive therapy over the course of their disease. It remains to be seen whether long-term Btk suppression, which could be a therapeutic strategy in indolent diseases like CLL/SLL, will result in infectious complications similar to those seen in XLA. Controlled studies are being planned to determine the role of Btk inhibitors in larger populations of patients.
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