Chronic Lymphocytic Leukemia: Will Recent Major Advances Lead to Cure?

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The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 1.0 category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity.

Valid January 1 - March 31, 2005.

Estimated time: 1 hour

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Educational Objectives
1. To review the incidence and natural history of chronic lymphocytic leukemia (CLL)
2. To understand various prognostic factors that affect life expectancy in CLL
3. To review the impact of newer therapeutic regimens in patients with CLL
4. To understand and differentiate the various medical complications associated with CLL and those which result from its treatment
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In 1967, Dameshek¹ described chronic lymphocytic leukemia (CLL) as an “accumulation of immunologically incompetent lymphocytes.” Chronic lymphocytic leukemia can best be described as a lymphoproliferative disorder. Characteristics often include lymphocytosis, lymphadenopathy, and splenomegaly. Most cases of CLL (95%) are B-cell neoplasms; the remaining cases are T-cell neoplasms.² The stage of B-cell disease is predictive of survival, with median survival ranging from over 10 years to less than 19 months,² and 9 years for the entire CLL patient population. Major advances have been made in the treatment of CLL over the last 20 years, precipitated by the development of purine analogs, monoclonal antibodies, and bone marrow transplantation. Expectations for treatment are gradually shifting from palliative goals to curative intent. A better understanding of the biology of the disease and treatment complications has improved supportive care for these patients as well.

INCIDENCE AND EPIDEMIOLOGY

B-cell CLL is the most frequently occurring leukemia in adults, comprising 30% of adult leukemias. The incidence in the Western Hemisphere is 3/100,000 individuals. It is very rare in Japan. For the geriatric population, the incidence in adults over the age of 70 is almost 50/100,000.³ Median age at diagnosis is 65 years. The risk of developing CLL increases with age. The risk for older men relative to older women is 2.8 to 1. Most patients are Caucasian and in the middle-income class. Some readers may be surprised to learn that long-term survival may be poor in some subpopulations.⁴

PATHOPHYSIOLOGY AND DIAGNOSIS

Chronic lymphocytic leukemia cells are malignant, small monoclonal B lymphocytes located in the mantle zone of lymphoid follicles.⁵ These cells express similar surface markers (identified by monoclonal antibodies against these antigens) as mature B lymphocytes. Normal B cells survive 7 days in the circulation; CLL cells survive 30-100 days. Features to note in CLL are the expression of cell surface markers such as CD5 (a T-cell marker), CD19, and CD23 (B-cell markers), dim CD20 expression, and minimal amounts of surface immunoglobulins (Igs) (IgM or IgD) with lambda or kappa light chains; these features are useful to differentiate CLL from other hematologic malignancies.⁶ Chronic lymphocytic leukemia cells are inefficient antigen-presenting cells due to a defective B-cell receptor and to low levels of co-stimulatory molecules.⁷

The hallmark of CLL is an elevated white blood cell count with absolute lymphocytosis in the peripheral blood. Minimal requirements established by the National Cancer Institute (NCI) for the diagnosis of CLL include an absolute lymphocyte count in the peripheral blood more than 5000 with a predominance of morphologically mature–appearing small lymphocytes persisting for at least 4 weeks, and a normocellular or hypercellular bone marrow with more than 30% lymphocytosis. The majority of the cells must express specific patterns of monoclonal B-cell markers as defined above. The most common chromosomal abnormality in CLL (60% of patients) involves deletion in chromosome 13q14.3 that is near the retinoblastoma gene (RB-1). Two tumor-suppressor genes, Leu-1 and Leu-2, have also been cloned in this region.⁸ Despite this chromosomal abnormality, these patients tend to have an indolent disease course. Deletions in chromosome 11q22-23 are associated with more aggressive disease and bulky nodal involvement.⁹ Advanced chemorefractory disease is associated with mutations of chromosome 17p13.3: the location of the p53 tumor-suppressor gene.¹⁰ Chronic lymphocytic leukemia cells can postpone apoptosis by over expression of Bcl-1 and Bcl-2 (genes involved in inhibiting apoptosis) or a mutation of the Bax gene. Rai and Binet^11,12 independently developed CLL staging systems.

The Rai staging system has five stages and the Binet staging system has three stages. In the Rai staging system, with long-term follow-up, it appears that stage IV patients have a slightly better prognosis than Rai stage III patients. Staging systems have been useful in assigning patients into various broad risk categories, but there is great variation in outcome within each stage. With early stage CLL (Hb ≥ 13, peripheral lymphocytes < 30,000, doubling time > 12 months), lifespan is not affected by the disease. The most extensively studied serum prognostic marker in CLL is beta-2 microglobulin (b2M). There is a linear relationship of worse prognosis as the b2M increases. Patients with serum b2M microglobulin less than 2 have 80% 15-year survival. Beta-2 microglobulin is also prognostically important in patients who have received prior therapy. The reason for the association of b2M and prognosis is unknown.

Soluble CD23 has also become important.¹³ CD23 is a hallmark of CLL cells and is an important antigen in differentiation of typical CLL from mantle cell leukemia. High levels of CD23 are associated with a poor prognosis. The impact of Ig mutation status on prognosis has also been evaluated.¹⁴ It appears that the naïve B-cell CLL population exists where there is no Ig mutation, as these cells have apparently not been influenced by the germinal centers of lymph nodes. These patients have a much shorter survival than the patients who have undergone Ig gene hypermutation. There is a strong association between the CD38 status and mutation.¹⁵ Patients whose cells have a mutated Ig gene tend to have very low levels of CD38 on their CLL cells, whereas patients with naïve B-cell CLL have higher levels and significantly worse prognosis. It is likely that there will be dramatic changes in the staging system if the prognostic significance of these serum factors or cellular factors is confirmed with extended follow-up. Two major groups have been working on the indications for treatment of patients with CLL: the International Workshop on CLL (IWCLL)¹⁶ and the NCI Working Group (NCI-WG).¹⁷ Comparison of the IWCLL and NCI-WG criteria for treatment and response are illustrated in the Table.

CLINICAL MANIFESTATIONS AND COMPLICATIONS OF CLL

It is believed that the recent increased incidence of early stage, asymptomatic CLL is due to the common practice of performing more blood counts for minor reasons. Most patients with CLL do not have disease-related symptoms at the time of the initial diagnosis. In fact, 20-30% of patients present with a normal physical exam. In symptomatic patients, the most common features include generalized lymphadenopathy, weight loss, and fatigue. Other symptoms may include loss of appetite and decreased exercise tolerance. Fever, night sweats, and documented infection are uncommon as initial symptoms but become more prominent as the disease progresses. Due to the accumulation of neoplastic B cells over time, patients who are asymptomatic at diagnosis may eventually develop lymphadenopathy, splenomegaly, and hepatomegaly. Furthermore, as a result of progressive bone marrow infiltration, hypersplenism, or autoimmune phenomenon, leukopenia along with concomitant anemia and thrombocytopenia may develop. Other complications during the course of the disease include infection, hypogammaglobulinemia, disease transformation, and second cancers.

PHYSICAL FINDINGS

The most common abnormal physical finding of CLL is lymphadenopathy. Approximately 50% of the patients will have lymphadenopathy and/or hepatosplenomegaly at presentation. Lymph node enlargement can be localized or generalized and can vary in size. Splenomegaly and/or hepatomegaly are present in 25-50% of the cases. Less commonly and usually late in the disease course, infiltration of the skin, eyelids, heart, pleura, lungs, and gastrointestinal (GI) tract may occur. As the disease progresses, massive lymphadenopathy may cause luminal obstruction including obstructive jaundice, dysphagia, obstructive uropathy, lower extremity edema, or partial bowel obstruction. The development of pleural effusions or ascites is associated with a poor prognosis.

COMPLICATIONS OF CLL

Patients with CLL may experience various complications as a result of disease progression. Infection is the most common cause of death in patients with CLL. Hypogammaglobulinemia is present in up to two-thirds of patients later in the course of the disease. All three classes of Ig (IgG, IgA, IgM) are usually decreased, although only one or two classes may be affected. Significant degrees of hypogammaglobulinemia and neutropenia result in increased susceptibility of patients with CLL to major bacterial infections. Streptococcus pneumoniae, Staphylococcus aureus, and Hemophilus influenzae are among the organisms commonly seen in patients with CLL who have not received immunosuppressive therapy. There has been a change in the spectrum of disease-causing bacteria resulting from the introduction of potent immunosuppressive agents. This includes both gram-negative organisms as well as opportunistic organisms such as Candida, Mycobac-terium, tuberculosis, Listeria, Pneumocystis carinii, cytomegalovirus, Aspergillus, and herpes virus.

Patients with CLL who are older than 65 and/or with advanced stage disease have the higher risk of infections and usually require prophylactic supportive care measures. Patients with CLL may undergo transformation of their disease into a more aggressive lymphoid malignancy. This occurs in 10-15% of patients with CLL. The most common of these are the Richter’s syndrome (5%) and prolymphocytic leukemia. Patients with Richter’s syndrome (large-cell lymphoma) often present with increasing lymphadenopathy, hepatosplenomegaly, fever, abdominal pain, weight loss, progressive anemia, and thrombocytopenia, with a rapidly increasing peripheral lymphocytosis and elevated lactate dehydrogenase (LDH). These patients have a median survival of 6 months. Patients with transformation to prolymphocytic leukemia present with progressive anemia, thrombocytopenia, lymphadenopathy, prolymphocytes in the peripheral blood (> 55%), hepatosplenomegaly, wasting syndrome, and increasing resistance to therapy. Other CLL transformations include acute lymphoblastic leukemia, plasma cell leukemia, multiple myeloma, and Hodgkin’s lymphoma.

Complications from autoimmune processes may also be observed in CLL. They include positive direct antiglobulin test (Coombs’ test), hemolytic anemia, thrombocytopenia, neutropenia, and, rarely, pure red-cell aplasia or agranulocytosis. The direct antiglobulin test is positive in up to 20% of patients with CLL during the course of their disease. Clinical hemolysis is seen in 50% of these cases. Autoimmune thrombocytopenia occurs in 2% of patients with CLL. Secondary malignancies have a higher incidence in patients with CLL than in the general population. Most frequent sites involve the skin (melanoma and carcinoma), lung (lung carcinoma), and GI tract. This is believed to be a consequence of potent immunosuppressive therapy. Other hematologic malignancies/disorders have also been reported in association with CLL.

THERAPY OF CLL

The current practice of initial close follow-up without treatment (watch and wait) is based on mature data from several large phase III trials that have shown no improvement in overall survival for asymptomatic, early-stage patients undergoing early therapeutic intervention with alkylator-based therapy.^18-20 Although newer regimens using the purine analog fludarabine demonstrate superior response rates in the upfront setting than traditional alkylator-based therapy, an overall survival advantage has not been shown for the use of fludarabine-based therapy as initial treatment. Outside of participation in early interventional clinical trials, treatment of CLL should occur at the time that the disease becomes symptomatic. The NCI criteria for initiation of treatment include the presence of nonautoimmune cytopenias (Rai stages III and IV), symptomatic lymphadenopathy or hepatosplenomegaly, disease-related B symptoms (fevers, night sweats, fatigue, or > 10% weight loss), an autoimmune hemolytic anemia, or thrombocytopenia not controlled with steroids.²¹ Until recently, the goal of therapy has been focused primarily on palliative chemotherapy, with only a small proportion of patients obtaining complete remission (CR). Novel agents, especially in combination, may be shifting the therapeutic goal toward obtaining CR and at least thinking about the possibility of curative intent.

TREATMENT USING CHEMOTHERAPY

The initial treatment of patients with symptomatic CLL had often involved therapy with chlorambucil, plus/minus prednisone. Chlorambucil slows disease progression, but does not increase survival, and increases the risk of acute myeloid leukemia (AML). The primary side effects of chlorambucil therapy are nausea and myelosuppression. The dose of chlorambucil is modified on an ongoing basis as dictated by blood counts and clinical response. Fludarabine has been the most extensively studied agent in CLL and is the only agent that is FDA approved for the treatment of the disease when there is failure to respond to an alkylating agent. Several large phase II studies in previously treated and untreated patients with CLL noted impressive response rates (30-80%), including a significant proportion of CRs ranging from 10-30%.^22-24 Fludarabine therapy has shown a higher complete response rate, prolongation of progression-free survival, and doubled remission duration, as compared to chlorambucil or the combination of cyclophosphamide, doxorubicin, and prednisone.^25-27

Almost 20% of patients with CLL do not respond to upfront fludarabine therapy; a significant number of these patients have a p53 mutation. Patients who achieve CR have a longer time to progression (3 1/2 years). Thus, current data suggest that fludarabine is the best first-line therapeutic option in the treatment of most patients with symptomatic CLL. However, it is important to remember that long-term overall survival advantage has yet to be demonstrated for the use of fludarabine over an alkylating agent in first-line therapy. Virtually all patients requiring therapy for CLL will eventually relapse with the development of symptomatic disease. Prospective and retrospective studies have shown an increased frequency of herpes virus infection with fludarabine in both untreated and previously treated patients.^28-30

Data supporting antimicrobial or antiviral prophylaxis are limited; these are generally not used unless the patient requires concurrent corticosteroids for previous autoimmune manifestations. The primary toxicities observed with fludarabine are myelosuppression and immune dysfunction leading to typical as well as opportunistic infections. Autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura have been seen in 5% of patients receiving fludarabine, and in some cases can be life threatening. In most cases, treatment with prednisone and discontinuation of fludarabine therapy are effective. Preclinical data suggest synergistic interaction between DNA damaging agents and purine analogs. Such synergism likely occurs as a result of alkylating-induced DNA damage and the subsequent inhibition of DNA repair by the purine analog. Combination studies with alkylating agents and purine analogs (cladribine, pentostatin, and fludarabine) have been performed. Several recent phase II reports have shown high clinical response rates with a combination of fludarabine and cyclophosphamide.^31,32

COMBINATIONS OF CHEMOTHERAPY WITH IMMUNOTHERAPY

The approval of both the anti-CD20 chimeric monoclonal antibody rituximab and the humanized anti-CD52 monoclonal antibody alemtuzumab has opened new horizons for upfront treatment of CLL. Rituximab is an anti-CD20 chimeric antibody that has been studied extensively in low-grade lymphomas in which responses were seen in 50% of patients.³³ Responses to rituximab in patients with CLL given standard lymphoma dosages have been marginal,³⁴ possibly because of different pharmacokinetics of rituximab in this disease or the dim expression of the CD20 target on CLL cells. However, the addition of monoclonal antibodies to upfront therapy of CLL has greatly increased the frequency of obtainable CR. Recent studies have combined rituximab with fludarabine-based therapies in previously untreated CLL with promising results.^35,36

A study undertaken by the M.D. Anderson Cancer Center in previously untreated patients with CLL added rituximab to attenuated doses of fludarabine and cyclophosphamide for 6 cycles.³⁷ In a preliminary report of 134 patients who completed treatment, 66% complete response and 95% overall response rates were seen. Several CRs (by polymerase chain reaction [PCR]) were demonstrated in this trial. Alemtuzumab is a humanized monoclonal antibody directed against the CD52 antigen. The FDA has recently approved alemtuzumab for the treatment of patients with CLL previously treated with alkylating agents and having fludarabine-refractory disease. The CD52 antigen is expressed on virtually all CLL cells as well as normal B and T lymphocytes, natural killer cells, and monocytes. In a large pivotal trial that led to alemtuzumab approval,³⁸ a 33% response rate and median survival of 16 months were observed in patients with CLL who had fludarabine-refractory disease. Among those patients responding to alemtuzumab in this trial, survival exceeded 32 months. Patients with large nodes (> 5 cm) and poor Eastern Cooperative Oncology Group (ECOG) performance status (≥ 2) had a significantly lower response to alemtuzumab. The antibody treatment can exacerbate pre-existing neutropenia and is associated with both bacterial and opportunistic infections.

HEMATOPOIETIC SUPPORT WITH GROWTH FACTORS

Anemia is a common laboratory finding in patients with CLL and becomes progressively more severe as the disease progresses. Therapy for CLL can further exacerbate a preexisting anemia, especially in the elderly population. The consequences are fatigue and dyspnea that often lead to great impairment in the patient’s quality of life. Randomized double-blind studies have demonstrated that recombinant erythropoietin may ameliorate anemia and the symptoms associated with it in patients with CLL.³⁹ Patients with CLL often have baseline neutropenia that can be further accentuated by chemotherapy. Nadir neutrophil counts can be of prolonged duration, particularly when combination therapies are given to patients with advanced-stage fludarabine-refractory disease. The administration of filgrastim or pegfilgrastim after chemotherapy can decrease the risk of neutropenia. In addition, one study demonstrated a decreased frequency of serious pulmonary infections in high-risk patients with CLL who are receiving filgrastim and fludarabine-based therapy relative to historical controls.⁴⁰ The use of both erythropoietin and granulocyte colony stimulating factors has now been routinely incorporated into our treatment regimens for patients at high risk for anemia and/or febrile neutropenia.

CONCLUSION

With the development of purine analogs and alkylating agent combinations that suggest superior response rates, new opportunities present themselves in this disease. The role of monoclonal antibodies and their integration into overall therapeutic plan are being actively explored. Further possibilities include the use of vaccines and cellular therapy. There are certainly grounds for optimism because of the increased number of options that are now available for patients in all stages of CLL. Finally, the bioavailability of an oral fludarabine along with that of oral alkylating agents suggests that such “pill-based” programs may make the delivery of CLL therapy easier—especially for our elderly patients—in the near future.