In January, New York-Presbyterian Hospital/Columbia University Medical Center opened the Center for Lymphoid Malignancies, a 3,700 square foot outpatient clinic, in the heart of Midtown Manhattan. The Center is solely focused on the treatment of all forms of Hodgkin and non-Hodgkin lymphoma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia/lymphoma. It was developed to provide patients with centralized multidisciplinary care and access to translational medicine to more precisely treat these complex lymphoid malignancies. Currently, the facility is engaged in over 20 phase I, II, and III clinical trials.
The ASCO Post talked with Owen A. O’Connor, MD, PhD, Director for the Center for Lymphoid Malignancies, Professor of Medicine and Experimental Therapeutics, and Co-Director of the Program for Lymphoid Development and Malignancies at the Herbert Irving Comprehensive Cancer Center at New York-Presbyterian Hospital/Columbia University Medical Center, about the goals of the new Center, how advances in more effective therapies for hematologic malignancies are extending survival rates, and the impact the federal budget sequester may have on future cancer advances.
Goals and Resources
What are your goals for the Center for Lymphoid Malignancies?
The Center for Lymphoid Malignancies is part of an institution-wide interest in building and bolstering a focus on hematologic malignancies with an effort to try to establish areas of expertise in the treatment of lymphoid malignancies, myeloid malignancies, multiple myeloma and amyloidosis, and myelodysplasia. Each of these settings is linked, where appropriate, to a program focused on bone marrow transplantation and immunobiology.
While providing traditional bread-and-butter care for patients with non-Hodgkin and Hodgkin lymphoma, the Center is unique in its focus on translational cancer medicine in an academic medical center. In this context, we can herald resources from all corners of the institution—scientific and clinical—to come up with practical solutions to even the most complex situations.
For example, we have a large laboratory effort focused on developing new drugs and, with Dr. Donald W. Landry [the Samuel Bard Chair of the Department of Medicine at the Columbia University College of Physicians and Surgeons], we have just finished filing patents on very promising new drugs that look to modulate the impact of nuclear factor-kappaB. This transcription factor is known to modulate over 400 different genes, many of which contribute to the misbehavior of cancer cells. Leveraging that kind of science, we’ve actually developed a new inhibitor, which in the laboratory seems to have remarkably potent effects against a whole variety of cancers, including lymphoma.
The intent of the Center is to try and bring this new science to the patient and translate these concepts as quickly as possible. For patients in whom conventional therapies haven’t achieved the desired goal, we have access to a host of promising new drugs and drug combinations that are beginning to target these diseases at their genetic and molecular roots. These new drugs have the potential to achieve meaningful clinical benefit with the possibility of less toxicity.
Another successful feature of our approach has been to exploit our large portfolio of over 20 clinical trials as a bridge to help patients who have disease that hasn’t responded well to conventional therapy get to an autologous or allogeneic stem cell transplant. Because many of these new drugs and drug combinations are not cross-resistant with conventional cytotoxic therapy, they offer a chance to achieve real remissions in the face of conventional chemotherapy resistance. For patients with multiply relapsed or refractory disease, successive lines of combination cytotoxic chemotherapy are rarely associated with the most favorable risk-benefit ratio.
New Challenges
Is the pace quickening regarding advances in treating hematologic cancers?
There is no question that the rate-limiting step in our ability to make improvements against these diseases is no longer our ability to identify relevant biology, and it’s no longer our ability to find the novel small molecules that target that biology. The major challenge is in trying to expedite the time it takes us to go from concept and proof-of-principle in the laboratory to opening and accruing the appropriate clinical trials in a way that will support the preclinical rationale and hasten the regulatory process as well.
There is also no question that the number of new drugs and potential new drug combinations for lymphoid malignancies has blossomed. But these times of truly remarkable riches create new challenges as well.
For example, recognizing that all these drugs will be used in some combination in the future, there are major questions regarding how best to combine them. Do we simply add everything onto an R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, prednisone) backbone, or should we be thinking about new treatment platforms that are not completely addicted to cytotoxic therapy and are instead based more on a biologically relevant rationale? Both approaches have merits. In rare diseases, the challenges are amplified even more.
Treatment Progress
Which blood cancers are seeing the most progress in terms of extended survival rates?
In the case of diseases that can potentially be cured, Hodgkin lymphoma is a great example where we have made enormous strides that have impacted natural history. Presently, there are basically two lines of investigation.
One strategy is to develop better risk-stratified approaches for the treatment of patients with Hodgkin disease, as is being shown now with the use of imaging modalities like positron-emission tomography (PET scanning). This sort of functional imaging can help us limit the amount of cytotoxic therapy patients are exposed to without compromising their long-term survival, and may help us define the optimal patient population to move forward to autologous stem cell transplant.
The second line of research involves the development of new drugs, and in particular novel antibody-drug conjugates like brentuximab vedotin (Adcetris). Brentuximab is a spectacular example of bringing together new concepts in monoclonal antibodies and the development of linkers, which allow the conjugation of highly cytotoxic small molecules that can very precisely deliver a toxic payload directly to the tumor. This antibody drug conjugate, which targets CD30, delivers monomethyl auristatin E to CD30-positive tumors like those seen in patients with Hodgkin disease and anaplastic large-cell lymphoma. It has been associated with very high response rates and durable remissions.
In many forms of non-Hodgkin lymphoma, such as follicular, lymphocytic, and marginal zone lymphomas, we are trying to move away from a chemotherapy-centric platform and adopt more immunologically or targeted therapies to convert these cancers into truly chronic diseases. We have already seen the impact of rituximab on follicular lymphoma and the change it has made in the natural history of that disease. I think the exciting question moving forward is, can we now develop chemotherapy-free platforms for many of these other subtypes of lymphoma?
New or older monoclonal antibodies coupled with new small molecules like Bruton’s tyrosine kinase (BTK) inhibitors that affect the B-cell receptor-signaling pathway, PI3-kinase inhibitors, and immunomodulatory drugs will create novel targeted approaches. I have no doubt that these strategies will allow us to manage these cancers as chronic diseases with less reliance on nonspecific cytotoxic chemotherapy. The field is moving at an amazingly fast pace, and I expect that in our lifetime we will see, and have already seen, substantial changes in the natural history of many forms of lymphoma.
Laboratory Research
Please talk about the focus of your laboratory work.
We have a program that is focusing on the biologic basis of select subtypes of lymphoma. For example, we are very focused on developing therapies specific for subtypes of diffuse large B-cell lymphoma that are derived from the germinal center.
We know that there’s an important pathogenetic pathway or axis, the BCL6:p53 axis, that is actually dysregulated in diffuse large B-cell lymphoma derived from the germinal center. In B cells derived from the germinal center, the oncogene BCL6 turns off the tumor-suppressor gene p53, which sets up the “DNA damage phenotype,” allowing for somatic hypermutation and isotype switching. This natural interaction generates diverse B cells capable of recognizing diverse antigens, but can lead to lymphomagenesis. Work in our laboratory, and in others, has shown that both BCL6 and p53 can be modulated in an epigenetic way by histone deacetylase inhibitors. These epigenetic modifiers have been shown to reverse the relationship by turning off the oncogene and turning on the p53 gene.
We are in the midst of a clinical trial with vorinostat (Zolinza) and niacinamide—a form of vitamin B3 that inhibits class III histone deacetylases—in patients with all types of aggressive lymphomas who had been heavily pretreated. To date, we have seen an overall response rate of 25%, which includes several durablecomplete remissions. There is little to no expectation that niacinamide will be active in this setting, and vorinostat has already been proven inactive in this setting. Interestingly, niacinamide has been shown to activate p53 by enforcing the accumulation of acetylated p53. We are now working with chemists at Columbia to find better ways to inhibit class I, II, and, III histone deacetylases and develop a platform of more potent drugs.
We also have a long-standing interest in developing better drugs for T-cell lymphoma. We’ve been doing a number of preclinical studies using pralatrexate (Folotyn)—the first drug approved for relapsed peripheral T-cell lymphoma—in a variety of combinations, including with the histone deacetylase inhibitor romidepsin (Istodax). These studies show that the pralatrexate/romidepsin combination seems to be remarkably synergistic and has resulted in cures and complete remissions in mice. Those studies have paved the way for the launch of a phase I clinical trial looking at this drug combination for T-cell lymphoma.
Impact of Sequestration
How will cancer research be affected by the federal sequestration cuts made to the National Institutes of Health budget?
There is no question that the enormous momentum we have achieved over the years in terms of thinking about how to develop novel therapeutics for cancer based on a biologic context has been absolutely remarkable. The reduction in funding at the federal level does threaten the pace of those developments over the next 5 to 10 years, and every physician, physician/scientist, and scientist involved in cancer research is going to be impacted.
We are going to have to be very innovative in how we maintain the trajectory of our progress for the benefit of patients, which may require us to look to private foundations for support, and possibly even philanthropy. It’s unfortunate that a lot of important programs supported by the government are going to be affected adversely.
In our field, it means that there is a potential that the present trajectory of our translational research for these challenging diseases will be adversely affected. This situation will require all of us to become involved in the political process to make sure the support is still there to maintain the momentum. Fortunately, most people working in this field are pretty clever, and I think in the end, we will find ways to make sure that nothing compromises our ambition to help every patient dealing with cancer. ■
Disclosure: Dr. O’Connor reported no potential conflicts of interset.
