Professor of Medicine, Deputy Director of Research Operations at the Moores Cancer Center at the University of California at San Diego
Can you briefly describe chronic lymphocytic leukemia?
Chronic lymphocytic leukemia (CLL) is a blood disorder caused by a malignancy of B cells, a type of white blood cell of the immune system. These cells can expand and cause problems with bone marrow and immune system functions. The leukemia results in an increase in the white blood cell count and, consequently, enlargement of the lymph nodes and the spleen. In addition, it can compete with the normal bone marrow cells in the bone marrow, interfering with the production of red blood cells and platelets.
One of the other problems with CLL is the development of immune deficiency. CLL cells can suppress immune function by decreasing levels of serum immunoglobulins. These are the proteins that bind to invading bacteria and viruses and help to defend against infection. Consequently, patients may be sensitive to infections.
Can you discuss the relationship between CLL and SLL?
Both CLL and SLL are considered to be non-Hodgkin lymphomas. Small lymphocytic lymphoma (SLL) has biologic and genetic factors that are very similar to CLL. The difference is that for patients with CLL there are excessive numbers of white blood cells in the blood that can be recognized by a simple blood test as an elevated number of lymphocytes. Both SLL and CLL can cause enlargement of lymph nodes and the spleen, which are increased in size due to excessive numbers of malignant B cells in these lymphoid tissues. Even though the blood lymphocyte count may not be elevated in patients with SLL, one generally can find malignant B cells in the blood using sensitive tests, such as flow cytometry. As such, the difference between SLL and CLL is somewhat semantic and is based on a patient’s lymphocyte count. The characteristics of the lymphoma cells or leukemia cells are virtually identical in terms of the types of proteins the malignant B cells express and the clinical problems that accumulation of such cells can cause over time.
For a patient with CLL, when and how is the decision made to begin treatment?
It is important to recognize that we have yet to clearly define curative strategies for patients with CLL. There is no treatment that I know of that is not associated with some risk. Therefore, one has to always balance the risks inherent in treatment versus the risks of not having treatment. This is a very important consideration to make. Some patients may have very indolent (slow-growing) disease that fails to progress, even after years of follow-up monitoring. If they were to incur a problem with therapy early on, that would be most unfortunate since their lifestyles or quality of life may not have been affected without therapy.
However, some patients are clearly progressing, and it is evident that it is not a question of whether they will require therapy, but a question of when they will require therapy. For those patients, a treatment plan can be effective and is currently recommended by a group of experts in the area called the International working group on Chronic Lymphocytic Leukemia (iwCLL).
The following indicate a need for therapy. First and foremost is whether the patient is having symptoms that are affecting his or her quality of life. The other noteworthy factor is how fast the disease is progressing. We look for the time it takes for the lymphocyte count to double. If that time is less than 12 months, some consideration should be made for treatment. If it is less than six months, then treatment should be recommended. Another consideration is lymph node size. Some patients may not have much of an increase in lymphocyte count but may have lymph nodes that are enlarging relatively quickly over time. If the lymph nodes are progressively increasing in size or become symptomatic, then that also could be used to justify initiating therapy.
Another important factor to note is that the leukemia can affect how well the bone marrow functions, which is a very significant complication. The leukemia cell may crowd out the spaces in the bone marrow needed for bone marrow cells to function properly, such that it does not produce sufficient numbers of red blood cells or platelets. This can result in either anemia or low platelet counts (thrombocytopenia). For patients who have this, it's important to make some therapy considerations. Anemia will certainly affect a person's quality of life. If it becomes very severe, it can also affect the patient's survival. This is also true for the platelet count, which can result in an increased tendency for bleeding, particularly if the platelet counts become too low. Therefore, if those signs of the disease are present, this would be an indication for initiating therapy.
Another subset of patients may develop autoimmune complications from the leukemia. About 10 percent of patients develop autoantibodies that attach to either their red blood cells or platelets and cause a marked reduction in the red blood cell or platelet count. The former can cause anemia, which can sometimes be life threatening, and the latter can cause a drop in the platelet count, which results in bleeding complications. For these patients, interventions are necessary on an urgent basis.
How has treatment for CLL changed over the years? How is it being treated today, and what are some new treatment advances?
Recently, there have been new therapies approved for patients with CLL. This is a very exciting time because the treatment for CLL is undergoing changes that improve the quality of treatment and the types of responses to treatment, as well as the survival of patients being treated.
A new monoclonal antibody was recently approved for treatment of patients with CLL. This drug is called obinutuzumab, or Gazyva and was approved in November 2013 as an initial therapy. This monoclonal antibody is similar to rituximab in that it binds to a protein, CD20, on the leukemia cell surface.
Another drug recently approved for treatment of patients with CLL is ibrutinib (Imbruvica), which is an orally administered medication. It is a small molecule that can target an enzyme called BTK within the leukemia cell. This enzyme conveys signals from the outside environment to the leukemia cell that are important for the leukemia cell's survival. If the signals are interfered with, the leukemic cells can eventually die. Another major effect of this drug is it prevents the leukemia cell from entering the lymph nodes. Consequently, patients who take this drug may experience very dramatic reductions of cells in the lymph nodes and spleen early on, because the leukemic cells are unable to return to the lymph nodes as effectively. Also recently approved is the drug idelalisib, which inhibits another enzyme in the leukemia cell that is involved in survival signaling. For patients with relapsed CLL, it is recommended that this drug be administered with rituximab, an anti-CD20 mAb. For patients with relapsed SLL, the FDA has allowed for patients to receive treatment with idelalisib alone.
We are also very excited about other agents that are being tested in clinic trials for CLL. Clearly, there are many more therapy options available today than we had even just a few years ago. Most of the types of treatments that were formerly available for patients caused bone marrow toxicity and, although they were effective treatments, patients could typically develop resistance to these drugs over time as well as poor tolerance to the drugs and problems with the bone marrow. These newer therapies provide alternative options for treatment that we believe will improve the survival rate for patients with this disease.
What is the future of CLL treatment?
I think the oral medications are attractive because of their ease of use. One of the problems that some of the newer oral medications is they have a hard time getting rid of all the leukemia/lymphoma cells. Most patients who are able to take the newer kinase inhibitors, for example, achieve partial remissions at least early on. As such, patients need to continue taking the drug to keep the disease at bay. Provided they continue taking the drug, these patients seem to be able to enjoy a progression-free survival period without experiencing increases in lymph node size or some of the symptoms that might be associated with the leukemia or lymphoma.
Are there any agents that you're particularly excited about coming out in the near or longer-term future?
I'm particularly excited about kinase inhibitors for the treatment of CLL. They have produced dramatic responses in patients who have shown resistance to standard chemotherapy. There is another category of drug called BCL-2 antagonists. BCL-2 is a protein that is overexpressed in leukemia, which prevents the leukemia cell from dying. If BCL-2 is interfered with, then the leukemia can die rather precipitously. There is a drug, ABT-199, currently being tested that can cause dramatic reductions in the leukemic cell count as well as dramatic reductions in leukemic cells in the lymph nodes and spleen. We have seen some patients who have been able to achieve complete remission without any evidence of detectable minimal residual disease (MRD). This means that when we look in the bone marrow with very sensitive tools, these patients do not have any detectable leukemic cells which is referred to as being MRD negative. For patients who achieve a complete remission that is MRD negative, we typically find that we can withhold therapy and they may have a prolonged period of time before they require additional therapy. Patients may achieve a long-lasting remission without having to take continuous lifelong therapy. So, this is an agent I'm excited about.
Lenalidomide (Revlimed), which is an immunomodulatory drug, is another agent. Recent research we conducted shows that this drug puts the brakes on leukemia cell division and can thus stop the leukemia cell from dividing. If you stop the leukemia cells from growing, then the leukemia starts to burn itself out and the numbers of cells can go down over time. It can also help to restore immune function, so patients may actually improve their resistance to infection.
We are also very excited about another antibody, cirmtuzumab vedotin (UC-961), which targets the protein ROR1 found on leukemia cells but not normal cells. Most antibodies used in treatment affect normal B cells and can result in more immune suppression. ROR1 is very important for the survival of leukemic cells. What I like about the ROR1 antibody is that it is specific for the leukemia or lymphoma cells and does not affect or should not affect the normal B cells or normal cells of the immune system. We are hoping that with this and other treatments, we might be able to eradicate this disease altogether. Our goal is to be able to eliminate the disease so that we can allow patients to live fruitful and productive lives without having to be under the threat of the disease or have to take continuous therapy in order to stay in a partial remission.
What advice would you give to a newly diagnosed patient?
I would advise newly diagnosed patientsto ask about some of the newer treatments that are now available. I encourage them to be aware of new developments in therapy. I would also say that if I had this disease, I would certainly want to be treated with the newer types of therapies. Because such therapy, and our understanding of how best to treat patients with this disease, is continuosly improving, treatment tomorrow most certainly would be better than treatment today. So, if you have indolent disease and lack any disease-related symptoms, I certainly would hold off therapy, even though we have these newer agents.
How are you involved with the Lymphoma Research Foundation, and why would you recommend the patient become involved with the organization?
I've been involved with the Lymphoma Research Foundation (LRF) for many years as a scientific advisor as well as a member of its prestigious Scientific Advisory Board. The Lymphoma Research Foundation have been very active in defining new therapies for patients with CLL and in funding research that leads to the development of new therapies for patients with CLL. I think that it’s very important that patients know that they can get assistance from organizations such as LRF.
Is there anything else you would like to add?
I'm excited about new developments in treatment, but I don't think we are done yet. Despite the fact that we have made some great advances in the treatment of CLL, we have work left to do to be able to eradicate this disease. I think it would be great if we can increase the level of research and be able to cure the disease so that patients do not continually require therapy. It is possible to cure this disease.