Bruton’s tyrosine kinase (BTK) inhibitor.

BTK (Bruton Tyrosine Kinase) a critical kinase involved in B-cell receptor signaling.

BTK is a downstream component of the B-cell receptor signaling pathway.

Covalently binds to Cys-481 near ATP binding domain of the BTK molecule, preventing B-cell receptor mediated survival signals.

The BTK inhibitor ibrutinib demonstrates sustained progression-free survival (PFS) and overall survival (OS) in chronic lymphocytic leukemia (CLL), regardless of patient’s high-risk cytogenetic status.

With up to 4 years of follow-up in ibrutunib the international phase III RESONATE trial, the 3-year PFS rate was 59% and the 3-year OS rate was 74%, according to long-term efficacy and safety findings.

Long-term results show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics.

In the RESONATE study ibrutinib versus ofatumumab in patients with relapsed or refractory CLL/small lymphocytic leukemia (SLL): reduced the risk of progression by 78% and the risk of death by 57% in the primary analysis, and significantly improved survival.

At interim analysisfound ibrutinib to be superior to ofatumumab for PFS and OS in CLL

Patients in the del(11q) subgroup CLL tend to have a more favorable outcome.

PFS outcomes were not statistically different for patients with del(17p), del(11q), or in those without cytogenetic abnormalities.

The PFS rate at 3 years was 53% for patients with del(17p), 66% for del(11q), and 58% for patients without these abnormalities.

PFS was comparable between patients with unmutated IGHV status and those with mutated IGHV status.

The 3-year PFS was 63% versus 66%, respectively.

Among the patients with unmutated IGHV status, 3-year PFS was 55% for patients with del(17p), 70% for del(11q), and 63% for patients without either abnormality.

Patients without TP53 mutations tended to have a longer PFS than those with TP53 mutations.

Patients who had not been heavily pretreated (2 or fewer previous therapies) had improved PFS compared to those who had more than 2 prior therapies.

Median OS was not reached for either arm, although OS was longer for ibrutinib than ofatumumab.

The overall response rate for ibrutinib was 91%.

Ibrutinib efficacious for del(17p) IGHV and del(11q) status in CLL.

The complete response (CR)/complete response with incomplete marrow recovery (CRi) rate was 9% with current follow-up and has increased over time.

The median treatment duration was 41 months with ibrutinib and 5 months with ofatumumab.

The most common adverse events of any grade include diarrhea, fatigue, cough, and upper respiratory infection,neutropenia, anemia, thrombocytopenia, hypertension, urinary tract infection, and diarrhea.

Its increased risk of atrial fibrillation, hypertension, and hemorrhage, limit its use

It is linked with potentially limiting cardiotoxicity, including profound hypertension (HTN).

Overall, 78.3% of ibrutinib users developed new or worsened HTN over a median of 30 months of follow up.

New HTN developed in 71.6% of ibrutinib users, with a time to 50% cumulative incidence of 4.2 months.

Among those without preceding HTN, 17.7% developed high-grade HTN (BP >160/100 mm Hg).

Ibrutinib is associated with a substantial increase in the incidence and severity of HTN, and that HTN development carries a higher risk of subsequent cardiotoxic events.

The prevalence of grade 3 adverse effects has generally declined over time, with incidence the highest during the first year.

The drug is associated with a more than six fold risk of cardiac arrhythmias, including atrial fibrillation, and potentially life-threatening ventricular arrhythmic events.

Cardiac arrhythmias are associated with myocardial fibrosis as indicated on cardiac MRI.

The prevalence of any-grade atrial fibrillation remains consistent over time with reported rates of 6%, 5%, 8%, and 8% over years 0-1, 1-2, 2-3, and >3, respectively.

The development of AF is associated with shorter event-free survival.

Rates of hypertension, however, increase over time, from 8% in year 0-1 to 22% in year >3.

By inhibiting B-cell receptor signaling it induces cells to undergo apoptosis.

Acts by interfering with key signaling events that are activated in CLL cells within the microenvironment acting very lymphoid tissues such as lymph nodes and spleen.

Interactions between the leukemia cells in the microenvironment activate the B-cell sectors on the CLL cells, which induces sequential activation of downstream signaling molecules,, such as the spleen tyrosine kinase, Bruton’s tyrosine kinase and PI3 kinases, promoting survival and proliferation of CLL.

BTK deficiency leads to severe hypogammaglobulinemia.

Trade name Imbruvica.

Adminstered once daily orally.

Ibrutinib has shown impressive activity early on, across the board, in B-cell malignancies from DLBCL, to CLL, Waldenstrom Macroglobulinemia, and particularly mantle cell lymphoma (MCL).

Approved for the treatment of CLL in patients who carry a deletion of chromosome 17 (17p).

Ibrutinib has been improved in the front-line setting and is especially useful high risk patients providing alternative to monoclonal antibodies administered alone or with chlorambucil.

Ibrutinib  continuous therapy in CLL only has an undetectable MRD of 5% with a significantly longer progressive free survival and overall survival suggesting BTK inhibitors can effectively modulate disease without reducing MRD in CLL.

Approved for mantle cell lymphoma or chronic lymphocytic leukemia who had received at least one prior treatment and for patients with chronic lymphocytic leukemia characterized by 17 P deletion.

Approved for monotherapy for treatment of patients with chronic graft versus host disease after failure of one or more lines of systemic therapy.

The global phase II trial with 560 mg daily until progression or toxicity in recurrent MCL, showed an ORR of 68% with a 21% CR and a median duration of of response 17.5 months.

In the above study acivity was seen regardless of the number of prior therapies, prior bortezomib exposure, or high risk disease.

Orally bioavailable agent, very well tolerated, with minimal hematological toxicity.

A key mediator in at least 3 critical B-cell prosurvival mechanisms: regulates apoptosis, cell adhesion, and lymphocyte migration and homing.

Bruton’s tyrosine kinase transduces signals from the B-cell receptor, a protien on the cell surface that allows B cells to bind to antigens.

Inhibits B cell receptor signaling within the malignant B cells with downstream mitigation of cell growth, proliferation, survival, adhesion, and migration.

B cell receptor signaling plays a role in normal development of B cells.

Inhibits differentiation and activation of T-helper 2 (Th2) T cells and skews development in favor of Th1 based immune responses.

An effective inhibitor of the B-cell receptor (BCR) signaling pathway and HAS clinical efficacy in the treatment of various B cell malignancies.

By inhibiting Bruton tyrosine kinase ibrutinib causes cell death and impairs migration and adhesion of malignant B cells.

Many B-cell malignancies, particularly CLL, mantle cell lymphoma, and activated B cell diffuse large B cell lymphoma have activation of the BCR signaling pathway and are particularly susceptible to the inhibition of this pathway.

High response rates alone or with rituximab in CLL, mantle cell lymphoma (MCL) and diffuse large cell B cell lymphoma.

Approved for mantle cell lymphoma.

High response rate in CLL of 70% and associated with low toxicity.

Ibrutinib overall response rate in treatment naive and relapsed /refractory CLL patients nearly 70% with a median follow-up of 20.3 months, and a 71% response in high-risk relapse/refractory patients at a median follow-up of 15.7 months: 26 months estimated overall survival 96% and 83%, respectively (Byrd JR et al).

Studies suggest rapid disease control in CLL in all anatomic sites at 6 months with 95% of patients achieving at least with 73% reduction in lymph node burden, and a median reduction in splenomegaly of 55%.

In a multicenter phase 3 study of 391 randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody : Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL (RESONATE).

In the above study Ibrutinib also significantly improved overall survival with a hazard ratio for death, 0.43,

In the above study at 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group.

In the above study the overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group, 42.6% vs. 4.1%,

The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the above study.

Atrial fibrillation and minor bleeding has been observed.

Atrial fibrillation occurs in up to 11% of patients in clinical trials.

Ibrutinib, used to treat mantle cell lymphoma, chronic lymphocytic leukemia (CLL), and other blood disorders, saw increased blood pressure within 6 months of starting the drug.

It caused the onset or worsening of hypertension in patients who had this complication regardless of the prescribed dose.

Associated with ibrutinib-related hypertension to an elevated risk of heart problems, including atrial fibrillation.

Nearly 72% of ibrutinib users were diagnosed with onset hypertension over median follow-up of 30 months after starting the drug.

The rate of new hypertension is 54% within 6 months.

High blood pressure was 13 times higher than would be expected in patients of similar age and heart conditions who were not taking ibrutinib.

Because of bleeding diathesis the drug should be avoided in patients on anticoagulations with warfarin.

Has been linked to an almost 20-fold increased risk of major bleeding in blood cancer patients taking concomitant antiplatelet and anticoagulation therapy in a clinical setting.

Inhibits platelet adhesion.

Treatment should be withheld 3-7 days before and after surgery.

Ibrutinib + Rituximab in high risk patients with CLL overall response rate of 83% (Burger J et al).

In patients with relapsed, refractory CLL disease with a 17p deletion median progression free survival duration with Ibritinib is about two years.

In patients with relapsed, refractory CLL disease with a 17p deletion experienced a 75% reduction in risk of disease progression or death.

In phase II trial of MCL greater than 70% overall response rate and 20% complete response rate (Wang M et al).

Studies have shown significant single agent activity in relapse the refractory mantle cell lymphoma.

In a single arm study in mantle cell lymphoma with relapse or refractory disease an overall response rate of 68%, complete response rate of 21% and a median fur ration of response 17.5 months.

A longerfollow up of the study showed a medium progression free survival of 13 months and median overall survival of 22.5 months, respectively.

For Waldenstrom’s macroglobulinemia responses are durable, reducing IgM levels and improving hemoglobin in patients with relapsed or refractory WM.

In patients with Waldenstrom’s with a CXCR4 mutation (appoximately 30% of such patients)are less likely to have a major response.

In relapsed DLCBL overall response rate of 28%: response rate 40% in activated B cell like group and 5.3% in germinal center B cell like group (Wilson W et al).

In patients with refractory or relapsed follicular lymphoma overall response rate 28% with 5% complete remissions , and 9 partial remissions.

In CLL lymph nodes shrink quickly within the first weeks of treatment, concomitant with a transient lymphocytosis in the bloodstream.

Redistributes CLL cells out of lymphoid tissue and into the peripheral blood, with they are eventually completed leading to remission.

Redistribution phenomenon is a class effect shared among BTK, SYK and PI3L inhibitors, and is caused by homing receptor signaling, such as that of chemokine receptors CXCR4, CXCR5 and adhesion molecules. A

Doses 420-560 mg orally daily (140 mg capsules).

For drugs that are moderate inhibitors of CYP3A, such as fluconazole, the dose should be decreased to140 mg daily.

The drug is safe and well tolerated with the most common adverse events being grade 1 and 2 diarrhea, rash, arthralgias, cramps, mouth sores and fatigue.

Hematologic toxicity is rather mild.

Can increase risk of bleeding.

Should not be given with an anticoagulant such as warfarin.

The response quality and frequency improved with ibrutunib such that after a median follow-up of 2 years the rate of complete responses approximately 2%, to 7%, and partial responses up to 80%.

Responses appear to be sustained with progression free survival of 75% at 26 months.

The combination of ibrutinib plus venetoclax yielded a high rate of undetectable minimal residual disease (MRD) when used as first-line treatment for chronic lymphocytic leukemia (CLL), according to the CAPTIVATE trial.

77% of patients in the CAPTIVATE trial had undetectable blood MRD after just six cycles of combined treatment.

In the above study 14 patients completing 12 cycles of the combination, 86% had undetectable bone marrow MRD, including all complete responders and most of the partial responders.

Approved for GVHD.

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