There is a need for new treatment options for patients whose treated chronic lymphocytic leukaemia or other B-cell malignancy has relapsed, or who do not respond to existing therapies
There is a need for new treatment options for patients whose treated chronic lymphocytic leukaemia or other B-cell malignancy has relapsed, or who do not respond to existing therapies. Bruton’s tyrosine kinase, or Btk, is a target that might have potential in these diseases, as it codes for a protein involved in B-cell development.
People with a mutation in this gene develop X-linked agammaglobulinaemia type 1, an immunodeficiency that results in mature B lymphocytes not being produced. In addition, Btk is overexpressed in chronic lymphocytic leukaemia, resulting in B-cell receptor signalling being aberrantly activated.
One drug that targets Btk, ibrutinib, is being developed by Pharmacyclics, in collaboration with Janssen.1 It is a selective and irreversible inhibitor of Btk, and is being investigated in chronic lymphocytic leukaemia and other blood cancers.
In one clinical trial, 56 patients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukaemia were given escalating oral doses of ibrutinib. Two schedules were tried, one in which subjects were given 28 days on, 7 days off, and the other in which continuous daily doses were administered.2 A fluorescent affinity probe was used to measure the occupancy of Btk in peripheral blood, and the dose escalated until the maximum tolerated dose was achieved, or until three dose levels above that at which full Btk occupancy was achieved.
The majority of adverse events were mild, and no dose-limiting events were observed, even after long-term dosing. Full Btk occupancy was seen at a dose of 2.5mg/kg/day, and the dose escalation carried on to 12.5mg/kg/day. It was rapidly absorbed and eliminated, with Btk occupancy being maintained for at least 24 hours. The objective response rate in the 50 evaluable patients was 60%, with 16% achieving a complete response. The median progression-free survival for the whole group was 13.6 months.
It has also been investigated in elderly patients, for whom standard treatment of fludarabine has a significant risk of morbidity and mortality. In a Phase Ib/II trial, both treatment naïve and relapsed or refractory patients aged over 65 with chronic lymphocytic leukaemia were given 420 or 840mg doses daily for 28 day cycles until their disease progressed.3 The higher dose was stopped once comparable activity and safety was demonstrated between the two doses in the relapsed or refractory patients.
Again, most adverse events were mild or moderate, and the most common were diarrhoea, nausea and fatigue. Nineteen of the 26 patients in the 420mg dosage group achieved a response, with two-thirds achieving a partial response, and two a complete response with no morphological evidence of the leukaemia in the marrow. A further three achieved nodal responses with lymphocytosis.
A Phase III trial is now under way, with ibrutinib being administered in combination with bendamustine and rituximab, compared with bendamustine and rituximab alone in relapsed or refractory chronic or small lymphocytic anaemia patients. It is also being investigated in other blood malignancies, including multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma and follicular lymphoma.
1. L.A. Honigberg et al. Proc. Natl Acad. Sci. 2010, 107, 13075
2. R.H. Advani et al. J. Clin. Oncol. 2013, 31, 88
3. J.C. Byrd et al. J. Clin. Oncol. 2012, 30 (suppl), Abst. 6507