Chronic lymphocytic leukemia

Kriachok I.A.


Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in Western countries with an incidence of 4.2/100,000/year [1]. The incidence increases to >30/100,000/year at an age of >80 years. The median age at diagnosis is 72 years. About 10% of CLL patients are reported to be younger than 55 years.

The guidelines for the diagnosis and treatment of chronic lymphocytic leukemia were revised by the International Workshop on CLL in 2008 (IWCLL). Criteria for CLL are as follows: the presence in the peripheral blood of 5 x 109/L monoclonal B lymphocytes for the at least 3 months. The clonality of the circulating B lymphocytes needs to be confirmed by flow cyto­metry [2]. Typical immunophenotype of CLL lymphocyte is CD5+, CD23+, CD43+/-, CD10-, CD19+, CD20 dim, slgdim+ and cyclin DI [3]. Bone marrow examination is not required for diagnosis and a CT scan not required for staging, but flow cytometry is crucial for correct diagnosis.

The first prognostic marker to be used in the clinical management of CLL was the Rai clinical staging system, published in 1975 [4]. This system was later followed by the Binet staging system, published in 1981 [5]. Both of these staging systems provide a basic framework for estimating prognosis and are factored into the current International Workshop on CLL guidelines for initiation of treatment [2].

Multiple factors, measured in standard clinical laboratory tests, affect the clinical course of CLL. These factors include lymphocyte count, lymphocyte doubling time, M level, sTK level, angiopoietin-2 (Ang-2) level, and soluble cluster designation markers (CD14, CD23, and CD49d). Other clinical markers that have been investigated as potential prognostic indicators include age, gender [6], lymphocyte doubling time [7], number of prolymphocytes [8], pattern of bone marrow involvement and percentage of smudge cells [9].

Approximately 80% of individuals with CLL have acquired chromosomal abnormalities within their malignant clone and can be categorized into five prognostic groups accordingly: deletion 13q (median survival, 133 months); deletion 11q (median survival, 79 months); trisomy 12 (median survival, 114 months); normal cytogenetics (median survival, 111 months); and deletion 17p (median survival, 32 months). Reciprocal chromosome translocations are described but are rare in CLL. A complex cytogenetic karyotype can be identified in ~I6% of patients and is commonly associated with poor prognostic features including CD38 expression and unmutated IgHV [10].

The outcome of patients with leukemic cells that use an unmutated IgVH gene is inferior to those patients with leukemic cells that use a mutated IgVH gene. In addition, the VH3.21 gene usage is an unfavorable prognostic marker independent of the IgVH mutational status. Leukemic cell expression of ZAP-70 and CD38 was found to correlate with the expression of unmutated IgVH genes and to predict a poor prognosis.

However, the association between expression of ZAP-70 or CD38 with the expression of unmutated IgVH genes is not absolute. It is uncertain whether leukemia-cell expression of unmutated IgVH genes or ZAP-70 predict the response to treatment or overall survival, once therapy is required. Taken together, further clinical trials are needed to standardize the assessment of these parameters and to determine whether they should affect the management of patients with CLL [2].

Recently 9 significantly mutated genes were identified that occurred in 5 core signaling pathways in which the genes play established roles: DNA damage repair and cell-cycle control (TP53, ATM), Notch signaling (FBXW7, NOTCH I), inflammatory pathways (MYD88, DDX3X, MAPKI), and RNA splicing/processing (SF3BI, DDX3X). Of these mutations, 5 of the mutated genes have been implicated in CLL for the first time [11].

Treatment of CLL ranges from periodic observation with treatment of infectious, hemorrhagic, or immunologic complications to a variety of therapeutic options, including steroids, alkylating agents, purine analogs, combination chemotherapy, monoclonal antibodies, and transplant options [12]. A meta­analysis of rando­mized trials showed no survival benefit for immediate versus delayed therapy for patients with early stage disease, nor for the use of combination regimens incorporating an anthracycline compared with a single-agent alkylator for advanced stage disease.

Indication for start of treatment are as follows: Binet stage C, Rai stages III or IV, Binet stage B or Rai stages I or II, with at least one of: splenomegaly, and or lymphadenopathy, when symptomatic, progressive, or massive (> 5 cm spleen, 10 cm nodes) progressive lymphocytosis (increase > 50% in 2 months or Lymphocyte Doubling Time < 6 months, AIHA or ITP unresponsive to corticosteroids, disease-related symptom (i.e., weight loss, significant fatigue, fever). Biological markers (e.g. cytogenetics, CD38, ZAP-70, IGVH mutations) are not an indication to start therapy (outside clinical trials). Response to therapy is the most important prognostic factor.

Recently substantial advances have been made in the treatment of CLL patients, most of which relate to monoclonal antibodies (MAb) alone and in combination with various chemotherapeutic drug combinations. Preferred treatment of choice (for patients with good performance status) is the combination of rituximab with fludarabine and cyclophosphamide (R-FC). Phase 2 clinical studies demonstrated that R-FC is the most effective combination to date in terms of achieving CR in CLL in previously untreated [13] and treated [14] patients.

Allogeneic stem cell transplant has been found to induce long-term disease-free survival in CLL patients with deletion 17p [15]. However, given the age of diagnosis and frequent presence of co-morbidities, transplant is not often an option for these patients. This has led to a search for non-p53 dependent agents for use in the management of CLL with deletion 17p.

Alemtuzumab, on the other hand, appears to work via a p53 independent pathway, and has demonstrated efficacy in 17p deleted or p53 mutated CLL [16]. Less effective for bulky (5 cm). 17p- patients who present with bulky lymphadenopathy remains a therapeutic challenge.

Ofatumumab, a human CD20 Mab that binds to another CD20 epitope, has shown promising results when used as a single agent in refractory CLL patients OR rate of approx 50% with a significantly longer survival in responding patients [17]. Several other MAbs are in early clinical testing or in the pipeline. In addition, a growing number of small molecules are being explored in clinical trials, providing hope for the future that CLL will be transformed into a disease that may be kept under control for very long periods of time.

For the selection of second-line treatment, the quality of first response plays a major role — if physically fit patients with refractory disease or relapse within 24 months after chemoimmunotherapy — or fludarabine-based combination therapy, the second remission should be used to proceed to an allogeneic stem cell transplant (especially indicated in very high risk [del(l7p), p53 mutation] and/or refractory disease [18].

If the patient is physically unfit, the treatment should be changed to an alternative regimen. The prognosis in this group is usually poor. If relapse is later than 24 months after the first therapy, the first-line therapy should be repeated.

Oblimersen is a drug that has been studied for use in CLL. An immunotoxin known as BL22 has shown a great deal of promise in treating hairy cell leukemia (HCL) in clinical trials. A newer version of this drug, known as HA22 (CAT-8015) is now being tested for use against CLL. The Bruton’s tyrosine kinase (BTK) inhibitor PCI 32765 (under development by Pharmacyclics) showed high rates of progression-free survival and low toxicity in patients with relapsed CLL, according to data presented here at American Society of Hematology (ASH) 53rd Annual Meeting. The drug is now in a phase 3 clinical trial.


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16. Stilgenbauer S, Zenz T, Winkler D, et al. Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2009; 27: 3994–4001.

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18. Dreger P, Corradini P, Kimby E, et al. Indications for allogenic stem cell transplantation in chronic lymphocytic leukemia: EBMT transplant consensus Leukemia 2007; 21: 12–17.

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