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European Commission has approved Imbruvica, a BTK inhibitor, for mantle cell lymphoma and chronic lymphocytic leukemia


The European Commission has approved Imbruvica ( Ibrutinib ) capsules, a first-in-class, once-daily, oral Bruton's tyrosine kinase ( BTK ) inhibitor.
Ibrutinib works by blocking BTK, a protein that helps certain cancer cells live and grow.
Imbruvica is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma ( MCL ), or adult patients with chronic lymphocytic leukaemia ( CLL ) who have received at least one prior therapy, or in first line in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy.

The approval of Imbruvica was based on data from the phase 3 ( RESONATE PCYC-1112 ) and phase 1b-2 ( PCYC-1102 ) studies in chronic lymphocytic leukemia, and the phase 2 study ( PCYC-1104 ) in mantle cell lymphoma.

RESONATE ( PCYC-1112 ) is a phase 3, multi-centre, international, open-label, randomised study that examined Ibrutinib as a single agent ( given orally ) versus Ofatumumab ( given intravenously ) in relapsed or refractory patients with chronic lymphocytic leukaemia ( n=391 ).
The results from the study showed that at a median follow up of 9.4 months, single agent Ibrutinib significantly improved progression-free survival ( PFS ), overall survival ( OS ) and overall response rate ( ORR ) in this difficult-to-treat patient population, regardless of baseline characteristics [ ORR was assessed according to the 2008 International Workshop on CLL ( IWCLL ) criteria by investigators and an independent review committee ( IRC )].
The median progression-free survival in the Ofatumumab arm was 8.1 months and was not reached in the Ibrutinib arm because progression events occurred more slowly. The progression-free survival results represent a 78% reduction in the risk of progression or death in patients treated with ibrutinib compared to Ofatumumab.
The median overall survival was not reached in either arm, but at a median follow up of 9.4 months the results showed a 57% reduction in the risk of death in patients receiving Ibrutinib versus those receiving Ofatumumab.
Results were consistent across all baseline sub-groups, including those with del17p.

The efficacy of Ibrutinib in patients with relapsed or refractory mantle cell lymphoma was evaluated in an open-label, multi-centre, single-arm phase 2 study ( PCYC-1104 ) of 111 treated patients.
An overall response rate of 68% was observed, with a complete response rate of 21% and a partial response rate of 47%. With a median follow up of 15.3 months, the median duration of response was 17.5 months; the median progression-free survival was 13.9 months.

The most commonly occurring adverse reactions ( greater than or equal to 20% ) were diarrhoea, musculoskeletal pain, upper respiratory tract infection, bruising, rash, nausea, pyrexia, neutropenia and constipation.
The most common grade 3/4 adverse reactions ( greater than or equal to 5% ) were anaemia, neutropenia, pneumonia and thrombocytopenia.

In most patients, chronic lymphocytic leukaemia is generally a slow-growing blood cancer of the white blood cells called B-lymphocytes. The median age at diagnosis is 72 years, and incidence rates among men and women in Europe are approximately 5.87 and 4.01 cases per 100,000 persons per year, respectively.
Median overall survival ranges between 18 months and more than 10 years according to the stage of disease.
Deletion 17p ( del17p ) and TP53 mutation are associated with aggressive, treatment-resistant disease. The abnormality results in the loss of function of a key gene, TP53. TP53 senses the presence of abnormal DNA and triggers either DNA repair mechanisms or cell death and is important in tumour suppression and the action of cytotoxic chemotherapy. Approximately five to eight percent of patients receiving first-line treatment have del17p at diagnosis. However, incidence of del17p and/or TP53 mutation rises to 29 to 52 percent in patients who have relapsed or refractory disease. The median predicted survival for patients with the del17p mutation or TP53 mutation is just two to three years.
CLL cells are found in both the lymphatic system and the blood. When the cancer cells are located mostly in the lymph nodes, the disease is called small lymphocytic lymphoma ( SLL ).
Both CLL and SLL are considered different manifestations of the same entity, as classified in the fourth edition of the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues.

Mantle cell lymphoma is considered a rare disease, characterised by high unmet need and small patient populations impacting fewer than one in 200,000 people in Europe and with a median age at diagnosis of 65.
Mantle cell lymphoma is much more predominant in men than women and accounts for three to 10% of all non-Hodgkin's lymphomas.
Median overall survival is typically three to four years, and only one to two years in patients following the first relapse.
Mntle cell lymphoma typically involves the lymph nodes, but can spread to other tissues, such as the bone marrow, liver, spleen and gastrointestinal tract. ( Xagena )

Source: Janssen-Cilag, 2014

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