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.
Continue Reading
AVL-292
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.
References
1. Niiro H, Clark EA. Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol. 2002;2(12):945-956.
2. Qiu Y, Kung H-J. Signaling network of the Btk family kinases. Oncogene. 2000;19:5651-5661.
3. Khan WN. Regulation of B lymphocyte development and activation by Bruton’s tyrosine kinase. Immunol Res. 2001;23:147-156.
4. Chun J-K, Lee TJ, Song JW, et al. Analysis of clinical presentations of Bruton disease: A review of 20 years of accumulated data from pediatric patients at Severance Hospital. Yonsei Med J. 2008;49(1):28-36.
5. Pan Z, Scheerens H, Li S-J, et al. Discovery of selective irreversible inhibitors of Bruton’s tyrosine kinase. Chem Med Chem. 2007;2:58-61.
6. Ponader S, Chen S-S, Buggy JJ, et al. Bruton’s tyrosine kinase inhibitor PCI-32765 thwarts chronic leukemia cell survival and tissue homing in vitro and in vivo. Blood. [published online ahead of print December 16, 2011].
7. Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci. 2010;107(29):13075-10380.
8. Advani RH, Sharman JP, Smith SM, et al. The BTK inhibitor PCI-32765 is highly active and well tolerated in patients (pts) with relapsed/refractory B cell malignancies: Final results from a phase I study. Ann Oncol. 2011;22(suppl 4):iv135-iv137.
9. Wang L, Martin P, Blum KA, et al. The Bruton’s tyrosine kinase inhibitor PCI-32765 is highly active as single-agent therapy in previously-treated mantle cell lymphoma (MCL): preliminary results of a phase II trial. Paper presented at: American Society of Hematology Annual Meeting; 2011 December 9-13; San Diego, California. Abstract 442.
10. Geisler C, Kolstad A, Laurell A, Räty R. Mantle cell lymphoma – does primary immunochemotherapy improve overall survival for younger patients? Leuk Lymphoma. 2009;50(8):1249-1256.
11. Chang BY, Francesco M, Magadala P, et al. Egress of CD19+ CD5+ cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor, PCI-32765, in mantle cell lymphoma patients [abstract]. (ASH Annual Meeting Abstracts). 2011;118. Abstract 954.
12. Brown JR. The treatment of relapsed refractory chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2011;2011:110-118.
13. Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for the treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117(23):6287-6296.
14. O’Brien S, Burger JA, Blum KA, et al. The Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765 induces durable responses in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): Follow-up of a phase Ib/II study [abstract]. (ASH Annual Meeting Abstracts). 2011;118. Abstract 983.
15. Singh J, Evans E, Karp R, et al. A targeted therapy (AVL-292) for Bruton’s tyrosine kinase in B-cell malignancies [abstract]. Haematologica. 2011;96(suppl 2):163.
16. Evans E, Tester R, Aslanian S, et al. Clinical development of AVL-292; a potent, selective covalent Btk inhibitor for the treatment of B cell malignancies [abstract]. Blood. (ASH Annual Meeting Abstracts). 2011;118. Abstract 3485
