Publication Date:
2019-11-13
Description:
Ibrutinib (Ibr) is a specific inhibitor of Bruton tyrosine kinase, a component of the B-cell receptor (BCR) signaling. Venetoclax (Veneto) inhibits the anti-apoptotic protein BCL2. Both drugs are highly effective as monotherapy against chronic lymphocytic leukemia (CLL) (Byrd NEJM, Roberts, NEJM, 2015 and Roberts, Blood, 2019) and clinical trials using the combination therapy are ongoing. An interesting clinical observation is that the tumor cell sensitivity to these two drugs differ between different anatomic compartments. While lymph node-resident CLL cells are more sensitive to ibr, circulating CLL cells in the peripheral blood are more sensitive to the action of veneto. When these two drugs are used in combination to treat relapsed/refractory (Hillman ASH 2018 and Kater EHA 2019) or previously untreated CLL patients (Jain NEJM 2019), rate of complete response significantly increases compared to single drug alone. Moreover, negativity of bone marrow minimal residual disease continues to improve over time. However, the reason behind these observed compartmental responses is largely unknown, and we investigated the differential response using an ex vivo model that promotes CLL proliferation (CLL proliferation model). A better understanding of how these two drugs synergize would eventually help develop other rational combination strategies. We established the ex vivo model using fibroblasts derived from the bone marrow of a CLL patient. In this model, CLL cells closely interact with the bone marrow fibroblasts (BMF) (Fig.1) and divide and proliferate for several generations, as measured by CFSE labeling. The culture, in some cases, may continue for 10 weeks before cell death ensues. With this ability to promote long-term cell proliferation, the model recapitulates one of the most salient features observed histologically in the "proliferation centers" of the CLL lymph nodes. With the proliferation model, we first tested the effects of ibrutinib on cell division/proliferation as well as cell viability in samples taken from 30 CLL patients consisting of 22 ibr-naïve (thus sensitive) and 8 ibr-relapsed (thus resistant) patients. We demonstrate that there was lack of a significant inhibition of ibr on cell viability. In comparison, Ibr markedly inhibited cell proliferation in cells from ibr-naïve/sensitive patients (p
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
Permalink