Bruton's Tyrosine Kinase: An Exciting New Target for Treatment of B-Cell Malignancies

Share this article:
Bruton's Tyrosine Kinase: An Exciting New Target for Treatment of B-Cell Malignancies
Bruton's Tyrosine Kinase: An Exciting New Target for Treatment of B-Cell Malignancies

Inhibition of Bruton's tyrosine kinase (Btk) is emerging as a promising mechanism for targeting B-cell malignancies such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) where the B-cell antigen receptor (BCR) is thought to possess an oncogenic role. BCR is composed of surface immunoglobulins that recognize foreign antigens. Upon binding to antigens, the downstream effector pathway, of which Btk is a central mediator, proceeds as shown in Figure 1.1 Non-receptor tyrosine kinases, including Btk, Src, Jak, Abl, Syk, and Fak, serve multiple roles in amplifying the signals from a number of surface receptors. Btk phosphorylates and activates phospholipase-Cλ (PLC-λ) and protein kinase C (PKC).2 The resulting expression of transcription factors, such as NF-κB, is critical to the survival, proliferation, and differentiation of B lymphocytes.3 Mutations in the gene encoding for Btk causes X-linked agammaglobulinemia (XLA) resulting in recurrent infections such as pneumonia, otitis media, skin infections, and septic arthritis.3

Figure 1.



A number of Btk inhibitors have been synthesized.5 Two compounds, PCI-32765 and AVL-292 have entered clinical trials and the results will be summarized here.

PCI-32765
PCI-32765 is an orally administered irreversible inhibitor of Btk. In a series of pre-clinical studies in CLL cells, the compound inhibited BCR- and chemokine receptor-related intracellular signals, chemokine secretion, cell migration, and survival.6 A fluorescent affinity probe for Btk demonstrated that occupancy of the kinase by PCI-32765 correlated with evidence of decreased BCR signaling.7

Fifty-six patients with relapsed/refractory B-cell malignancies were enrolled in a Phase I dose escalation trial of PCI-32765 to define a maximum tolerated dose or a dose that is three dose levels above attainment of full Btk occupancy.8 Daily dosing in 28-day cycles followed by a 7-day holiday was evaluated in five dose cohorts, and a once-daily continuous dosing was evaluated in two dose cohorts. Possibly related grade 3 or higher (adverse events) AEs occurred in 16% of patients, with less than 7% experiencing grade 3 or higher neutropenia or thrombocytopenia. No dose-limiting toxicity was identified. Objective responses (complete response plus partial response) were observed in 30 of 50 (60%) evaluable patients, regardless of dose level or histology:

  • CLL/small lymphocytic lymphoma (SLL) 11/14 (79%)
  • Follicular lymphoma 6/13 (46%)
  • MCL 7/9 (78%)
  • Diffuse large B-cell lymphoma (DLBCL) 2/7 (29%)
  • Waldenström macroglobulinemia 3/4 (75%)
  • MALT or marginal zone lymphoma 1/3 (33%)

At the time of data analysis, with median follow-up of 6 months, 25 patients continued to take the study medication without disease progression.   

Page 1 of 3
Share this article:

Related Resources

You must be a registered member of Cancer Therapy Advisor to post a comment.

CTA Community Poll

Sign Up for Free e-newsletters

Regimen and Drug Listings

GET FULL LISTINGS OF TREATMENT Regimens and Drug INFORMATION

Bone Cancer Regimens Drugs
Brain Cancer Regimens Drugs
Breast Cancer Regimens Drugs
Endocrine Cancer Regimens Drugs
Gastrointestinal Cancer Regimens Drugs
Genitourinary Cancer Regimens Drugs
Gynecologic Cancer Regimens Drugs
Head and Neck Cancer Regimens Drugs
Hematologic Cancer Regimens Drugs
Lung Cancer Regimens Drugs
Other Cancers Regimens
Rare Cancers Regimens
Skin Cancer Regimens Drugs

More in Hematologic Cancers

FDA Expands Ibrutinib Use in Chronic Lymphocytic Leukemia

FDA Expands Ibrutinib Use in Chronic Lymphocytic Leukemia

People with chronic lymphocytic leukemia and 17p deletion can now get the therapy.

FDA Approves Zydelig for Three Hematologic Cancers

FDA Approves Zydelig for Three Hematologic Cancers

The FDA has approved Zydelig for relapsed chronic lymphocytic leukemia, follicular B-cell non-Hodgkin lymphoma, and small lymphocytic lymphoma.

Early Stem-Cell Transplantation, Ongoing Therapy Increase Survival in Multiple Myeloma

Early Stem-Cell Transplantation, Ongoing Therapy Increase Survival in ...

Patients with multiple myeloma experienced survival benefits when treated autologous stem-cell transplantation after induction therapy.