Teaching a young dog new tricks: Story of a kinase and its inhibitor
The development of normal lymphocytes is a well-orchestrated process, that begins in the bone marrow. This process involves a functional antigen receptor (B-cell receptor or T-cell receptor) and a dozen of intermediators, including adaptor proteins and kinases that form a network of signaling pathways inside the cells. One such intermediator in the B-cells is Burton's tyrosine kinase (BTK). While BTK was identified decades earlier, its role in the development of B-cells was first elucidated by the association of its mutation with a severe immunodeficiency, called X-linked agammaglobulemia (XLA) by two back-to-back landmark papers in 1993. It turns out that BTK is not only critical for the development of normal B-cells, it also plays an important role in maintaining the survival of malignant B-cells. Therefore, blocking the activity of BTK can potentially be a way to treat B-cell malignancies. Indeed, ibrutinib, a small molecule that binds permanently to BTK, inhibits the function of BTK and drives the chronic lymphocytic leukemia (CLL, a B-cell leukemia) cells into self destruction. In a pivotal clinical trial, ibrutinib alone resulted in clinical response in ~70% of the patients with mantle cell lymphoma. This result led to the FDA approval of ibrutinib to treat patients with relapsed/refractory mantle cell lymphoma in 2013. This is quite remarkable on several points. First, ibrutinib is another proof that targeted therapy can be very effective in treating cancer. In addition, this successful story occurred because of the tremendous basic research works on the biology and pathobiology of diseases. Second, ibrutinib is an oral drug, which makes it very convenient for the patients. Its low toxicities also make it possible for long term use. Subsequent clinical trials further demonstrated the efficacy of ibrutinib in treating CLL and Waldenstrom’s macroglobulinemia; both now are FDA approved indications for ibrutinib treatment.
After allogeneic transplant, both donor B-cells and T-cells can play critical roles in the process of chronic graft-versus-host disease (cGVHD) by generating immunity against the recipient. While the standard immuno-suppressive agents such as steroid, calcineurin inhibitor, and mTOR inhibitor can help to manage cGVHD, prolonged use of these agents carry significant toxicities and they do not work all the time. Therefore, other less toxic ways to treat cGVHD are needed. One candidate is ibrutinib. In the pre-clinical study, ibrutinib inhibits both the BTK in B-cells, and the Interleukin-2-inducible T-cell kinase (ITK) in the Tcells. Therefore, ibrutinib can potentially block the deteriorating effects of GVHD-triggering donor B-cells and T-cells at the same time. In a clinical trial lead by Dr. David Miklos, 42 patients with steroid dependent refractory cGVHD were treated with ibrutinib. Nearly 70% of the patients had clinical benefit from the ibrutinib, by either improvement of the GVHD symptoms or ability to taper the dose of systemic steroid. The study also showed that patients tolerated ibrutinib quite well. Supported by this study, the FDA has approved the use of ibrutinib for the additional indication of chronic GVHD in August 2017. Additional trials are being conducted to test whether ibrutinib can be used in the GVHD prophylactic setting. With our ongoing work, we anticipate this young dog will learn more new tricks that can help our patients.
Ongoing Trials on Ibrutinib’s Effect on GVHD
BMT 302: A Phase 2 Study of Ibrutinib Maintenance AYer Reduced-Intensity Conditioning and Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia (Andrew Rezvani, MD)
BMT 316: Optimizing Post-Allogeneic Hematopoietic Cell Transplant Outcomes for Lymphoma Using Ibrutinib (David Miklos, MD, PhD)