Ashbel Smith Professor of Medicine and in the Department of Leukemia at UT MD Anderson Cancer Center
Would you briefly describe chronic lymphocytic leukemia?
Chronic lymphocytic leukemia (CLL) is a chronic leukemia with which patients can live for many years. CLL involves the lymphocytes, which are one type of white blood cell that is normally circulating. However, with CLL, the lymphocytes are leukemic; and begin to accumulate, so the typical manifestation is an elevated white blood cell count. It may also involve lymph nodes, appearing as a lymphadenopathy or spleen enlargement. And by definition, because it's leukemia, it involves the bone marrow where the cells are manufactured.
Most people with this disease present in an early stage and without symptoms. One of the most common ways in which people are diagnosed with CLL is during a routine physical examination when the doctor has ordered some blood work and an elevated white count is found or when the doctor is examining the patient and notices some enlarged lymph nodes.
How common is CLL?
CLL is the most common leukemia in adults in the Western world. For reasons unknown, CLL is relatively rare in Asia. The median age at diagnosis is approximately 70 years. The lower end of the age range can be as low as 20, which would be very rare. Typically, patients are in their 50s to 70s when they are diagnosed.
How is CLL typically treated?
Initially, CLL is not treated, which makes it somewhat unusual for leukemia because this is probably one of the only leukemias for which we do not necessarily initiate therapy at the time of diagnosis. Many patients are asymptomatic and can live a long time without symptoms. Treating patients in whom the disease is not causing any problems would just be exposing them to side effects of therapy and not necessarily benefiting them if they initially feel fine. The vast majority of patients are not treated at the time of diagnosis.
There are published guidelines for when to treat CLL and, to a very large extent, what they say is commonsense: you treat the disease when it is starting to cause a problem. For example, we consider patients for treatment if they have bulky lymph nodes that are unsightly or uncomfortable, if they have very rapidly progressing disease, or if they start to develop anemia or low platelets because they have such extensive involvement of the bone marrow. If the bone marrow is now focused on making these leukemic cells, the other cell lines begin to suffer; platelet counts or hemoglobin can be reduced, which can cause symptoms.
What chemotherapy regimens do these patients usually receive, starting with the low risk?
Low-risk asymptomatic patients aren't treated. If patients need treatment, therapy selection, to some extent, depends on their age and comorbidities. The most common standard front-line therapy in Europe and in the United States is a three-drug regimen called FCR, which stands for fludarabine, cyclophosphamide, and rituximab (Rituxan), a combination of two chemotherapy drugs — the first two — and a monoclonal antibody.
A monoclonal antibody is not chemotherapy. It is actually a protein designed to attach itself to a complementary protein on the surface of the leukemic cell. When this occurs it increases the effect of the chemotherapy.
Treatment selection is made in consideration of age and comorbidities because there are side effects from FCR, including significant myelosuppression or temporary lowering of the blood counts due to the chemotherapy. Considering the biggest risk associated with lowering a patient’s blood counts is infection, it would be feasible that an 80-year-old patient who gets pneumonia could be rendered bedridden; whereas, a 60-year-old might not even have to be hospitalized. In general, myelosuppression and infection are generally associated with more significant symptoms and problems in older people.
In the United States there is not one standard of care for older patients or patients with comorbidities, although I'm stressing that it is not specifically age related. A 75-year-old patient who plays tennis three times a week is very different than a 75-year-old patient who comes to the clinic with high blood pressure and diabetes and has had bypass or open heart surgery. You can imagine that those two patients, even though they are the same age, might not tolerate chemotherapy the same way. So we take into consideration both age and the comorbidities such as the other diseases or other problems that the patient has when deciding if they are a good candidate for FCR.
What are the current main areas of research for CLL?
One of the hottest areas of research is new drug development; in particular, what are called the B-cell receptor inhibitors. There are two main kinds of lymphocytes normally, B and T. CLL involves leukemia of the B lymphocytes, and they have a receptor on their surface called the B-cell receptor. Once triggered, that receptor sends a very strong signal to the cell to survive and proliferate. If you can inhibit that signal in a B-cell malignancy, like CLL or lymphoma, that might have a positive effect on the outcome of the disease. There are a number of enzymes that are in the pathway of that receptor so that when the receptor gets signaled, it passes down its message through various enzymes or what are called kinases; therefore, there are several different potential targets in this pathway that can be targeted to interrupt this signal.
The two drugs that are the farthest along in development — and are both in potential FDA approval pivotal trials — are ibrutinib and idelalisib. Ibrutinib binds to one of the proteins in that pathway called BTK, so it is a BTK inhibitor. Idelalisib (formerly GS-1101 or CAL-101) targets PI3 kinase. These are both oral agents, and they are both considered B-cell receptor inhibitors; they attach themselves and inhibit different kinases in that pathway.
These drugs are not myelosuppressive, so that is very exciting because one of the most common complications of chemotherapy is myelosuppression and infection. Patients who start treatment with anemia or low platelets often have significant improvement in those counts while on treatment.
They are interesting drugs because the pattern of response you see is different than chemotherapy. When patients start taking them, the first thing that happens is a dramatic shrinkage in the lymph nodes; but at the same time, the lymphocyte count in the peripheral blood actually goes up. Part of that is related to leukemic cells coming out of the lymph nodes into the blood where over time then they will slowly die off.
The good news is that patients with CLL can walk around with very elevated lymphocytes — 200,000 to 300,000 — and really have no symptoms. It is important to be aware of this pattern of response so it is not presumed that a patient’s leukemia is getting worse, causing the treatment to be stopped too early.
The toxicity profiles are a bit different between the two agents. With ibrutinib, the most common side effect is diarrhea, but it tends to be very mild and stop even though the patients continue the drug. With the idelalisib, the most common side effect is elevation in liver function tests, which is something the patient would not even notice. If that is observed, the drug is stopped, and once the abnormality has resolved, the drug is given at a lower dose, and most patients can stay on therapy.
These are exciting drugs because they are oral, they are not myelosuppressive, they do not have much toxicity, and they are working incredibly well even in people who we would consider to be very high risk; namely, those who have failed prior chemotherapy regimens. Both of these drugs are continued indefinitely or until the patient progresses.
Can you talk about the importance of clinical trials, and are there any specific trials you wish to discuss?
I think clinical trials are very important for a number of reasons. From a patient point of view, it gives people access to new drugs before they are on the market; the patients who perhaps never would have gotten into remission with standard therapy because they were so refractory are continuing in remission.
From a scientific point of view, clinical trials are very important because they provide information about whether new drugs or treatments work. Once an FDA pivotal randomized trial is conducted, we have usually already gained experience with a new drug, we know the dose, we know the toxicity, and now the trial is comparing it to a standard regimen to see if it is actually better.
Now not all trials involve investigational drugs. Sometimes two relatively standard regimens that are both acceptable are compared to determine which one actually provides better results.
What advice would you give to a newly diagnosed patient?
It is important to know your options and get an opinion from an expert in the field. Physicians in practice treat many, many tumors; and, leukemia is a very small subset of the patients they generally see. They see more patients with the common diseases like lung cancer, breast cancer, colon cancer, etc. It is a good idea to get a second opinion from a major medical center and an expert in the field because CLL is a relatively rare disease.
The other advantage of getting a second opinion from a major medical center and an expert in the field is that it allows you to find out about clinical trials that might be available.
How are you involved with the Lymphoma Research Foundation (LRF)? And why would you recommend the patient become involved with LRF?
I am on the Scientific Advisory Board for LRF, and I would recommend that patients seek information from LRF because LRF is a great source of information for someone with lymphoma or CLL. LRF has different types of information that can be offered to patients, including information about the disease and information about clinical trials. It just provides a wealth of information for patients.