Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma.


Bruton’s tyrosine kinase (BTK) is a mediator of the B-cell–receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin’s lymphoma, including mantle-cell lymphoma.


In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety.


The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.


Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma.

Source: NEJM


Ibrutinib Highly Active in Patients with Chronic Lymphocytic Leukemia with 17p Deletion.

The targeted agent ibrutinib produced rapid and durable control of disease in both treatment-naïve and relapsed/refractory patients with 17p deletion chronic lymphocytic leukemia, according to the results of a study presented at the 12th International Conference on Malignant Lymphoma held June 19-22, 2013 in Lugano, Switzerland.

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia. The American Cancer Society estimates that approximately 15,000 people will be diagnosed with CLL this year. Currently, there are approximately 95,000 people in the United States living with CLL.

CLL is characterized by the production of atypical lymphocytes. Lymphocytes are specialized immune cells that exist in two forms: B- and T-cells. These cells are produced in the bone marrow and each serves a specific function in aiding the body to fight infection. The large majority of CLL cases involve mature B-lymphocytes that tend to live much longer than normal. B-lymphocytes accumulate in the blood, bone marrow, lymph nodes, and spleen. This results in overcrowding of these areas and suppression of the formation and function of blood and immune cells. Additionally, the cancerous lymphocytes themselves do not function normally, leading to a further reduction in the body’s ability to fight infection.

Although there are effective treatments for CLL, some populations are harder to treat and tend to have worse outcomes. Many elderly patients are unable to tolerate current aggressive standard treatments. Also, individuals with a deletion in the short arm of chromosome 17 (referred to as del 17p) have poor outcomes with chemotherapy.

Ibrutinib is a selective inhibitor of Bruton’s tyrosine kinase, a component of the B-cell receptor signaling pathway that plays a key role in the development and progression of CLL. In other words, the targeted therapy attacks the pathway that mediates disease progression.

Researchers conducted a phase II, single-agent study that included 29 patients with del 17p CLL—15 who were treatment-naïve and 14 with relapsed/refractory disease. Patients were treated with 420?mg of ibrutinib daily until disease progression and response was evaluated at 6?months and every 6?months thereafter. After a median follow-up of 9 months, the results showed a promising response.

At 6 months, 88 percent of 25 evaluable patients had a nodal response (defined as 70% median reduction in lymph node size), 48 percent had a partial response by International Workshop on CLL (IWCLL) criteria, and 40 percent had a partial response with lymphocytosis. One patient had progressive disease (presumed transformation). Nodal response was observed in 93 percent of the patients with relapsed/refractory disease and in 82 percent of treatment-naive patients.

The estimated event-free survival at 12 months was 90 percent. All patients showed a reduction in splenomegaly, with a median reduction in spleen volume of 446 mL (46%) from baseline. At 6 months, the researchers repeated bone marrow biopsy and fluorescence in situ hybridization (FISH) measurement in 23 patients. The bone marrow biopsy revealted that tumor burden decreased by a median 76 percent (from baseline) as assessed by immunohistochemistry for CD79a. FISH was used to quantify the percentage of tumor cells with the 17p deletion—at 6 months, there was a median reduction of 55 percent in 15 out of 18 patients, no change in 1 patient, and an increase in 3 patients.

Treatment was tolerated—non-hematologic toxicities of grade 3 or higher were observed in 14 percent of patients. Two deaths occurred during the study, but were not considered treatment-related.

The researchers concluded that single-agent ibrutinib is effective in treatment-naïve and relapsed/refractory patients with del 17p CLL and produces rapid and durable control of disease. Research will be ongoing to evaluate single-agent inbrutinib as a strategy for this group of high-risk patients.



Wiestner A, Farooqui M, Valdez J, et al. Single agent ibrutinib (PCI-32765) is highly effective in chronic lymphocytic leukemia patients with 17p deletion. Hematological Oncology: Special Issue: 12th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, June 19–22, 2013. 31 (SI): 96-150. Abstract 008.




Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia.


The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few 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.


We conducted a phase 1b–2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg.


Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%.


Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions.

Source: NEJM