World experts on CLL/SLL shared their knowledge with Australian patients in September 2015
International Speakers included:
Dr Adrian Wiestner
Adrian Wiestner graduated from the University of Basel with a M.D. in 1992 and a Ph.D. in 1997. He completed his residency in the Department of Internal Medicine at University Hospital in Basel, Switzerland from 1997 to 2000. He is certified by the Swiss Medical Board in Internal Medicine and by the Educational Commission for Foreign Medical Graduates. He joined the NHLBI as a haematology fellow in 2000, became a clinical fellow at the National Cancer Institute in 2003, and joined the NHLBI as a tenure-track Investigator in 2004. He has been an attending physician in the NHLBI’s Haematology Branch since 2004. Dr. Wiestner has authored or co-authored more than 60 papers and is currently conducting multiple clinical research studies.
Combining medical training as a haematologist with a doctoral degree, Dr. Wiestner’s goal is to align his research in lymphoid malignancies as closely as possible with clinical translation. Using samples of blood, bone marrow, and lymph nodes collected from patients during clinical trials for chronic lymphocytic leukemia (CLL) and the related mantle cell lymphoma (MCL), he aims to improve therapeutic strategies by identifying the critical molecular drivers of disease pathogenesis and understanding the impact of existing therapies on tumour cell stress responses and the development of drug resistance.
Using gene expression profiling of cells from MCL patients undergoing bortezomib treatment, Dr. Wiestner and his colleagues demonstrated that bortezomib, through inhibition of proteasome function, causes an abnormal accumulation of proteins. This results in two overlapping stress responses in these tumours; one due to the increased protein load in the endoplasmic reticulum (ER) and the other due to the generation of reactive oxygen species (ROS). Patients who respond well to the drug show a very strong antioxidant response, suggesting that tumour cells are overwhelmed rather than incapable of fighting back. Resistant cells appear to have a higher basal level of antioxidant gene expression, suggesting that they are more competent in handling ROS stress. Complementary insights into bortezomib resistance came from the generation of MCL cell lines that are 50-100 times less sensitive to the drug. Dr. Wiestner and his colleagues have shown that the acquisition of bortezomib resistance, which is a slow and reversible process, correlates with an increase in the expression of genes that are typically expressed in plasma cells, including genes coding for protein chaperones and antioxidant functions. This “partial plasma cell program” endows cells with the capacity to handle high protein load and could be the key to MCL drug resistance. Clinically, a subset of bortezomib-resistant MCL indeed does show features of plasma cell differentiation, and is less sensitive to bortezomib.
For CLL, a number of studies using in vitro models have put forth candidate pathways that may be important for disease progression. Using gene expression profiling and analysis of signalling proteins, Dr. Wiestner and his colleagues demonstrated that CLL cells in the lymph node appear to be activated through a few distinct pathways, one of which operates through the B cell receptor. B cell receptor signalling inhibitors have been developed and have potent activity in certain lymphoid malignancies including CLL and MCL. Based on these observations, Dr. Wiestner’s team designed a clinical trial to study CLL cells isolated from the lymph node before and after treatment with B-cell receptor inhibitors. The goal is to study and contrast the impact of these inhibitors on the B-cell receptor pathway in patients that respond to therapy or develop resistance.
Dr. Wiestner’s group has also investigated the anti-tumour effects of lenalidomide in CLL and found that the drug induces a strikingly potent immune response that results in tumour shrinkage. Learning more about the biological action of single therapeutics allows for the design of rational combination therapies that have the potential to overcome the resistance that often develops with single agent therapies over time.
Dr. Wiestner’s group has several ongoing clinical studies being conducted at the NIH clinical center (www.clinicalcenter.nih.gov) in Bethesda, MD that are open to patients from all over the United States. These clinical trials range in scope from observational studies for untreated CLL patients (NCT00923507) to treatment trials using novel and emerging drugs such as the BTK inhibitor ibrutinib (formerly PCI-32765; NCT01500733) or the fully humanized anti CD20 antibody ofatumumab (NCT01145209). For participant information please refer to www.clinicaltrials.gov, and enter the NCT identifier into the search field.
Dr William Wierda
Dr Wierda is a professor and center medical director for the department of leukaemia at MD Anderson Cancer Center. Dr. Wierda earned his PhD in 1992 and MD in 1993 from University of Health Sciences at Chicago Medical School and his post-graduate education in internal medicine was at Duke University. This was followed by a fellowship in Haematology/Oncology at University of California at San Diego, where he was trained under the mentorship of Dr. Thomas Kipps. Dr. Wierda’s particular research interests in CLL are prognostic factors and developing prognostic models in CLL, immune and gene therapies for patients with CLL, developing chemoimmunotherapy regimens and treatment strategies for relapsed and refractory patients with CLL.
Dr. Wierda is head of the CLL section in the department of leukaemia, where he is directing the clinical and translational efforts in CLL and low-grade lymphoproliferative diseases. Dr. Wierda is also the director of the clinical core and clinical research of the CLL Research Consortium (CRC), a multicentre PO1 project headed by Dr. Thomas Kipps at UCSD. In his role, Dr. Wierda is directing and coordinating CLL-related clinical research activities at the participating sites, including Mayo Clinic, The Ohio State University, UCSD, Dana Farber Cancer Institute, Long Island Jewish Hospital, as well as MD Anderson Cancer Center. For the past several years he has served on the NCCN Lymphoma Panel providing leadership and recommendations for CLL treatment in the NCCN guidelines. He has published many articles in high-impact peer-reviewed journals on various clinical and translational aspects of CLL and drug development and given numerous lectures at national and international scientific meetings.
Dr Brian Koffman
Dr. Koffman, a well-known
doctor, educator and clinical professor turned patient has dedicated himself to
teaching and helping the CLL community since his diagnosis in 2005. Dr. Koffman
believes that his dual status as a physician and patient provides a unique
experience and understanding which allows him to provide clear explanations of
complex issues and to advocate for his fellow patients and inform his fellow
healthcare providers. This is especially important in view of the rapidly
changing therapeutic landscape. Besides his medical degree, Dr. Koffman has a
Master of Science in Medical Education. Dr. Koffman is also a practicing family
doctor, board certified in Canada and USA, a retired clinical professor in
family medicine at the Keck School of Medicine, USC, and the former medical
director of the non-profit medical educational organization, Primary Care
Network. Dr. Koffman serves as the unpaid medical director of the CLL Society