ASCO Update: Chronic Lymphocytic Leukemia

ABSTRACT: These reports are written by oncologists from Pacific Shores Medical Group (a large group practice in Long Beach, California). The reports are primarily based on notes taken at the American Society of Clinical Oncology yearly meeting (San Francisco, May 2001). The reports include our impressions (shown in italic type) of the clinical significance of the studies. The information is intended to help you get updated on new developments in oncology. The coverage of the meeting is not meant to be comprehensive, but rather focused on highlights that we consider most interesting or relevant.

Notes on CLL

At the Meet the Professor Session, Dr. George Canellos of the Dana-Farber Cancer Institute, Harvard Medical School, discussed his view about current issues relating to the diagnosis and management of chronic lymphocytic leukemia (CLL) and its different stages. Dr. Canellos is an experienced clinician who manages many patients with CLL, and some pearls that we could gather during his presentation follow.

1. Autoimmune phenomena, particularly when they are severe, including hemolytic anemia, thrombocytopenia, and at times even pulmonary involvement with bronchiolitis obliterans, require immune suppression primarily with prednisone, although cyclosporine and azathioprine (Imuran) can also be necessary, depending on the severity of the problem.

2. Prolymphocytic transformation is fairly common and is managed generally with a lymphoma (CHOP) type of chemotherapy regimen. In addition to known prognostic factors that indicate a more serious course, such as short doubling time of lymphocyte proliferation, advanced age, and prolymphocytic histology, the role of certain new prognostic factors was mentioned such as the presence of CD38. The latter is associated with a poorer prognosis.

3. Cytogenetic abnormalities can also be associated with a more serious course, but testing is generally not indicated in the initial management. Bone marrow examination is also optional at the outset, and most studies can now be done in the peripheral blood.

4. Chemotherapy options: Dr. Canellos uses low-dose weekly doxorubicin in patients with advanced disease who would not otherwise tolerate other more myelosuppressive or aggressive regimens. Similarly, in frail patients who need therapy, he has utilized fludarabine (Fludara) on a relatively low-dose weekly regimen. Rituximab (Rituxan) can be helpful in autoimmune anemia, including conditions such as cold agglutinin disease. He does not think that the management of T-CLL, a rare condition, differs much from the treatment of B-CLL.

In patients who have had previous immune thrombocytopenia or immune hemolytic anemia, which is now not active, he indicated that fludarabine is not necessarily contraindicated. He said that there are no data to indicate that fludarabine would be unsafe in patients with CLL who have had prior autoimmune disorders.

Indication for Treatment

Treatment is seldom indicated in CLL patients with low-stage, early disease whose presentation is asymptomatic lymphocytosis. Many patients are being discovered now at this stage, given that routine blood tests are often done at yearly physicals. Reasons to initiate therapy include constitutional symptoms such as fatigue or weight loss, bone marrow failure, autoimmune phenomena, progressive symptomatic splenomegaly, and lymphadenopathy. Absolute lymphocytosis is seldom an indication for therapy except in patients whose lymphocyte count doubles rapidly, within a year.

Treatment Options in CLL

With regard to therapy, there is no gold standard. Dr. Canellos emphasized that none of the currently available treatment methods has provided a prolongation of overall survival in studies completed and published to date. Potential initial treatments include alkylating agents and steroids, and nucleoside analogs, mainly fludarabine, with or without steroids. The combination of nucleoside analogs and alkylating agents is too toxic because of its association with a high incidence of serious infections. New agents include rituximab, a CD20 antibody, with some activity in CLL. The activity, however, is somewhat limited because of the fact that CD20 is generally not very highly expressed in CLL cells.

The advent of alemtuzumab (Campath-1H), a humanized monoclonal CD52 antibody, offers a potential new avenue (see also p. 3). The antibody is active but also toxic, and especially during the initial treatment, it can be associated with fevers, rigors, rash, nausea, and vomiting. These side effects, however, can be manageable with the use of antihistamines, acetaminophen, antiemetics, and other measures. Investigators are trying to determine the best way to use this agent, which is given as an IV infusion usually once a week. Alemtuzumab is active in CLL with an 89% objective response rate in previously untreated patients and a 33% objective response rate and 59% stability in patients who have had heavy previous treatment.

Bone Marrow Transplantation in CLL

Bone marrow transplantation, generally allogeneic transplantation (from a matched donor), is associated with long-term remissions in about one half of patients, but it is associated with very high morbidity and mortality rates. In fact, at least 30% of patients die from high-dose therapy and allogeneic transplantation, and therefore this treatment modality needs to be approached with extreme caution. More recently, non-myeloablative chemotherapy regimens used to induce allotransplantation grafting with graft-vs-leukemia effects have gained some favor. However this approach remains experimental.

New Approaches in CLL

Additional new approaches include gene therapy to induce high expression of CD40 and subsequent immunogenicity of leukemic cells.

The fact that the PCL-2 gene product is consistently overexpressed in CLL has led to the development of antisense agents that are currently in phase II testing. These offer an interesting avenue for potential intervention.

Gemcitabine (Gemzar), a drug originally approved for treatment of pancreatic cancer, turns out to be active in CLL as well as in Hodgkin’s disease, and its future in the treatment of these diseases seems bright. Currently, studies are testing the use of gemcitabine in patients with Hodgkin’s disease as well as lymphoproliferative disorders such as CLL. Several other investigational agents were discussed, but are not yet close to the clinical arena.

It is our impression from this presentation that it is important to be cautious in the initial management of CLL, since many patients do not require intervention. Being gentle in "breaking the news" of CLL is critical because this is a disorder that often has a good prognosis, and patients should not be inappropriately "labeled" as having a serious disease with a poor prognosis. Despite the name leukemia, CLL is often a chronic, relatively benign disorder.

The advent of Campath, a CD52 monoclonal antibody, clearly offers a new and effective method of therapy albeit with important side effects. The side effects and toxicity profile, however, are manageable and will continue to be improved as we learn how to use this treatment better. Additional promising agents currently available and being tested further are gemcitabine and rituximab. Fludarabine is also a very effective therapy, but it has to be used with careful attention to potential side effects, namely immune suppression with incidents of a variety of infections, particularly opportunistic infections including Pneumocystis carinii pneumonia (PCP) and herpes zoster. Among prognostic factors, CD38 is an important new marker associated with a more serious course.

In many patients, using the "art of medicine" approach can pay high dividends. In this regard, low-dose weekly doxorubicin, low-dose weekly fludarabine, and various permutations utilizing rituximab and alkylating-agent-based therapy can be very rewarding. The use of an alkylating agent in combination with fludarabine is discouraged because of the high incidence of serious infections.

High-dose therapy with allogeneic transplantation from a matched donor can induce durable remissions in patients with CLL. However, this approach is associated with at least a 30% mortality and, in some series, up to 50% mortality, making this treatment extraordinarily toxic. About 50% of patients who survive this approach will have a long-term remission, but some of them will still develop recurrence many years, sometimes more than 10 years, after therapy.

High-dose therapy with autologous stem cell transplantation is better tolerated, but it is associated with less efficacy with frequent recurrence. It appears that graft-vs-host disease associated with graft-vs-leukemia effect is a component of the efficacy of transplantation and, of course, is not present when an autotransplant is done. Finally, rituximab may be helpful in patients with CLL who have autoimmune complications.