Editors: Hillman, Robert S.; Ault, Kenneth A.; Rinder, Henry M.Title: Hematology in Clinical Practice, 4th EditionCopyright ©2005 McGraw-Hill> Table of Contents > Part II - White Blood Cell Disorders > Chapter 21 - Chronic Lymphocytic Leukemias

Chapter 21

Chronic Lymphocytic LeukemiasThe chronic lymphocytic leukemias (CLLs) are relatively common lymphoproliferative diseases with several unique clinical manifestations. They are different from the acute leukemias in terms of both prognosis and therapy. Understanding the various forms of CLL requires familiarity with the major lymphocyte subsets.

LYMPHOCYTE SUBSETSThree major lymphocyte subsets are found in blood: T cells (approximately 70 - 80% of lymphocytes), B cells (10 - 15%), and natural killer (NK) cells (10 - 15%). T cells are responsible for cell-mediated immune reactions and regulation of the immune system; B cells are responsible for antibody production; NK cells seem to function in a relatively nonspecific way to defend against some viral infections and perhaps against malignantly transformed cells (see Chapter 19).T cells are subdivided into two major additional subsets identified by the markers CD4 (40 - 50%) and CD8 (20 - 30%) and referred to as helper and suppressor T cells, respectively. �Additional markers, each identified by a corresponding set of monoclonal antibodies, can be used to distinguish all of these major subsets. These markers are summarized in Table 21-1. In addition to the lineage-specific markers, there are several nonlineage-specific markers whose presence or absence is particularly useful in classifying lymphoproliferative disorders. These are summarized in Table 21-2. For the purposes of describing the CLLs, the following phenotypes are particularly important.

B CellsMature B cells are identified by their expression of CD19 and CD20 as well as surface immunoglobulin (sIg) heavy chain (predominantly IgM and IgD) and immunoglobulin light chain (κ or λ). Normal B cells express either κ or λ light chains but never both, and the normal ratio of κ- to λ-expressing cells is about 3:2. Therefore, when a population of B cells expresses only one light chain, it can be presumed to be clonal and likely malignant. Even minor distortions of the normal relationship between κ and λ light chain expression (clonal excess) can be used to indicate the presence of an abnormal B-cell clone.

A. CD5 B CELLSCD5 B cells are a subset of B cells that comprise 20 - 30% of the normal B-cell population in blood. CD5 is a marker usually associated with T cells. This CD5 B-cell subset has been shown to have a propensity to produce autoantibodies such as rheumatoid factor, antiDNA, antiphospholipids, and so on. They are present in large numbers during fetal development of the immune system and when the immune system is reconstituted following marrow transplantation or intensive chemotherapy. They are of importance because most B-cell CLLs have this phenotype.

T CellsMature T cells are identified by their expression of several different markers. The most important is CD3, which is part of the T-cell antigen receptor (TCR) analogous to B-cell sIg. In addition to CD3 the TCR contains other proteins known as α-, β-, γ-, and δ-chains. The expression of these chains is not nearly as good a clonal indicator as is B-cell sIg light chain because the vast majority of normal T cells express α- and β-chains only. The presence of γ- and δ-chains on a population of T cells is rare but, if found, can be an indicator of clonality. The other major T-cell markers include CD2, CD5, and CD7. Normal mature T cells express all of these, whereas abnormal T cells frequently lack one marker or express it in abnormal amounts. This condition usually indicates a malignancy. The other two major T-cell markers, CD4 and CD8, are found together in normal thymocytes (and some T-cell malignancies) but are mutually exclusive on mature T cells.

A. CD4 T CELLSCD4 T cells represent 60% of T cells in blood (40 - 50% of lymphocytes) and are usually referred to as “helper†T cells. This terminology is outdated and somewhat misleading �but is useful conceptually. The true role of CD4 on T cells is in recognizing HLA-DR on macrophages and B cells. T-cell-specific retroviruses such as human T-cell leukemia virus (HTLV) and HIV use CD4 as a receptor. Thus, this subset is involved in both the lymphoproliferative and the immunodestructive processes mediated by these viruses.

Table 21-1. Clinically useful lineage-specific lymphocyte markers.Markers Lymphocyte Subset Clinical UtilityCD3 All mature T cells T-cell CLLCD4 “Helper†T cells� T-cell CLL, AIDSCD8 “Suppressor†T cells� T-cell CLL, AIDSCD19 Mature and immature B cellsB-cell CLLCD20 Mature B cells B-cell CLLsIg B cells B-cell CLL

B. CD8 T CELLSCD8 T cells represent about 30–40% of T cells (20–40% of lymphocytes) and are referred to as “suppressor†T cells, again a misleading term. The role of CD8 is in �recognizing HLA-A and -B antigens on macrophages and B cells. It is the CD8 subset that is mostly involved in graft rejection, killing of tumor cells, and virus-infected cells. Most of the “atypical†lymphocytes seen in response to viral infections are the CD8 subset. Their �numbers are more highly variable in normal individuals in response to even mild viral infections and stress. They are much less commonly involved in malignant processes.

Table 21-2. Clinically useful nonlineage-specific lymphocyte markers.Marker Lymphocyte Subsets Clinical UtilityCD1 Thymocytes (immature T cells) T-ALLCD2 T cells and NK cells T-ALL and CLLCD5 T cells and some B cells T-ALL, T-CLL, and B-CLLCD7 T cells and NK cells T-ALL, T-CLLCD10 Pre–B cells and immature

granulocytesCommon-ALL

CD16 NK cells and granulocytes NK cellsCD23 Activated B cells B-CLL

CD38 Activated lymphocytes and plasma cells

Present in many leukemias but not on normal resting lymphocytes

CD56 NK cells and some T cells Best marker for NK cellsCD57 Some cytotoxic T cells T γ-CLLHLA-DR

B cells and activated T cells Present in most leukemias but not on resting T cells

C. CYTOTOXIC T CELLSCytotoxic T cells are a subset of CD8 T cells that specialize in killing tumor cells and virus-infected cells. They are usually activated (ie, they express activation antigens such as HLA-DR and CD38) and frequently express CD57. They can be markedly increased in patients with acute viral infections and are the malignant cell type in large granular lymphocytic (LGL) leukemia or T γ lymphocytosis.

NK CELLSNK cells represent only 10 - 20% of blood lymphocytes. They are best characterized by their expression of markers such as CD16, CD56, CD57, and, more importantly, their lack of CD3. True NK cells are not T cells and have not rearranged their TCR genes. They are capable of killing tumor cells and some virus-infected cells by a mechanism similar to that of cytotoxic T cells. They do not, however, use the immune recognition mechanisms of T cells and do not display immunologic memory. They identify abnormal cells by their characteristic deficiency of HLA class I histocompatability antigens. They can be thought of as transitional between the nonspecific role of macrophages and the specific recognition found in T cells and B cells. They represent an important host defense mechanism and can be markedly expanded in response to malignancy and infection. True clonal malignancies involving NK cells are rare.There are examples of CLL that correspond to each of the major lymphocyte subsets. Each of these has distinct clinical and pathophysiologic manifestations.

CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)In general, CLL is a disease of older adults (median age 65 - 68 years, with 90% over 40 years of age), and its major clinical manifestation is an increase in the number of circulating lymphocytes. The patient with CLL may have varying degrees of lymphadenopathy, ranging from very little to massive.The distinction between CLL and lymphoma is largely semantic. Patients presenting with a marked increase in circulating lymphocytes (see Color Plate 50) and less adenopathy are diagnosed as having CLL, whereas patients presenting with prominent adenopathy or a tumor mass and near normal white blood counts may be diagnosed as having lymphoma. If a lymph node biopsy is done, it will be read as typical of a “small cell†or diffuse well-�differentiate lymphocytic lymphoma. Even when the lymphocyte count is normal, such �patients will have some detectable circulating lymphoma cells and thus can be said also to have CLL. Also from a clinical standpoint, there is little difference between patients presenting with lymphoma and those presenting with leukemia. They are, therefore, almost certainly the same disease.CLL may also present with minimal leukemia or adenopathy but a major immunologic or hematologic abnormality. The most common is a B- or T-cell immunodeficiency state resulting in recurrent infections, autoimmune thrombocytopenia or hemolytic anemia, and, less often, granulocytopenia or aplastic anemia. Thus, CLL must be considered in the differential diagnosis of patients with any of these disorders and must be ruled in or out by analysis of lymphocyte markers. It is not uncommon to find patients with a normal level of circulating lymphocytes that are nevertheless largely CLL cells.

There are major genetic and environmental influences on the type of CLL that occurs in different populations. In parts of Japan, T-cell CLL (specifically of the CD4 type) is by far the most prevalent. This situation has been associated with the prevalence of HTLV-1 virus as well as a genetic predisposition in some peoples. Conversely, in the Americas and in Europe, the most common form of CLL is of B-cell origin. The awareness, and perhaps the incidence, of T-cell CLL seems to be increasing throughout the world, however. Although specific viruses have not yet been implicated in most forms of the disease, it is likely that more will be identified.

B-Cell CLLB-cell CLL is the most common form of CLL in the West. It is almost entirely a disease of older adults. With the increasing frequency of lymphocyte marker studies, however, it is being diagnosed earlier and in younger patients. In fact, small collections of B cells with the characteristic surface markers of B-cell CLL (CD19, CD20, and CD5 positive) can be found in 3–4% of otherwise normal individuals over the age of 40. The frequency of small populations of circulating CLL B cells is even higher in family members of CLL patients (~13%), suggesting an inherited susceptibility. This does not translate, however, into a comparable increase in the incidence of clinical disease in family members. Some other stimulus, such as repetitive antigenic stimulation, is required to promote a leukemic subclone from these otherwise normal B cells. B-cell CLL typically has a long natural history and, therefore, is considered the least “malignant†of the lymphoproliferative disorders.�

Clinical FeaturesB-cell CLL patients may present with nonspecific symptoms of malaise, easy fatigability, weight loss, and night sweats. More often, they seek medical attention because of lymphadenopathy or the condition is picked up on a routine complete blood count (CBC). Symptoms and signs associated with CLL are dependent on the tumor burden both in terms of its metabolic demands and mechanical effects of collections of lymphocytes in the nodes, liver, spleen, and marrow. Very large lymph nodes can occasionally result in airway obstruction. With extensive marrow involvement, patients develop anemia, thrombocytopenia, or pancytopenia. At the same time, most patients with CLL are asymptomatic despite the presence of extraordinarily high numbers of circulating lymphocytes. The absolute lymphocyte count can easily reach levels of 100,000– 300,000/µL without impinging on the production of other hematopoietic cell lines.B-cell CLL patients can also present because of a functional abnormality of their immune system. They are usually hypogammaglobulinemic secondary to a suppression of normal B-cell proliferation and are subject to recurrent bacterial infections with encapsulated organisms (eg, Streptococcus pneumoniae). More often, however, they present with an autoimmune manifestation such as autoimmune thrombocytopenia or a Coombs positive hemolytic anemia.

Laboratory StudiesA routine CBC may be all that is needed to diagnose B-cell CLL. The typical pattern is a marked increase in the number of mature-appearing lymphocytes in circulation with little or no impact on the red blood cell, granulocyte, or platelet counts. Still, the definitive diagnosis requires immunophenotyping and gene rearrangement studies.In patients with very high absolute lymphocyte counts, most cells in circulation will be found to be mature B cells that mark for CD19, CD20, and CD23. In addition, the most striking and nearly diagnostic finding is the presence of CD5, together with abnormally low amounts of sIg. The sIg is usually IgM or IgD or both, less frequently IgG; and always only a single

immunoglobulin light chain, either κ or λ, is present. Thus, the finding of an increased number of B cells expressing CD5, with low levels of sIg and a single immunoglobulin light chain is diagnostic of B-cell CLL (Figure 21-1).

A. IMMUNOGLOBULIN GENE REARRANGEMENTThe diagnosis of a clonal B-cell CLL can also be made by testing DNA for immunoglobulin gene rearrangement. All B-cell CLLs show rearrangements of one or both immunoglobulin heavy chain genes and either the κ or λ or both immunoglobulin light chain genes. In addition, about 10% of B-cell clones show rearrangement of TCR β-chain gene but rarely the TCR γ-chain gene. Although this technique is both extremely sensitive and specific, it is usually unnecessary in the patient who presents with a large tumor burden. It is of value in situations where there are very few leukemic cells, whether at presentation or following chemotherapy or transplantation. Although the measurement of phenotypic markers and immunoglobulin light chain expression can accurately detect a clone of B cells that makes up only 1% of the circulating population, gene rearrangement studies are more sensitive.Recent studies have shown that B-CLL cells use a highly restricted set of germ-line immunoglobulin (VH) genes. These are the same genes that are associated with autoreactivity, which may help to explain the frequent occurrence of autoimmune hemolytic anemia and autoimmune thrombocytopenia in these patients. In approximately 50% of CLL patients the germ line genes show high levels of somatic mutation, indicating that the cells arose from more mature B cell precursors. The presence of these somatic mutations has been associated with a better prognosis. CLL with unmutated genes has a median survival of 8–10 years, whereas the mutated genotype is associated with a 25-year median survival. Surrogate markers for the unmutated genotype include high level of expression of surface CD38 and cytoplasmic expression of ZAP-70, a protein involved in intracellular signaling from the antigen receptor. Thus measurement of these markers is becoming an important element in evaluating the patient with CLL.

B. CYTOGENETIC ANALYSISObtaining cytogenetic analysis of CLL cells has been difficult owing to their very low proliferation in response to mitogens. In the studies that have been done, a variety of chromosomal abnormalities have been described, the most common being deletions on chromosomes 11, 13, and 17, and trisomy 12. With the advent of FISH technology, these same chromosomal abnormalities can be detected in 82% of patients. CLL patients with 17p-, 11q-, or multiple cytogenetic abnormalities have a shorter survival. The 17p- abnormality may involve loss of the p53 gene, which is important in the tumor response to purine nucleoside analogues. The clinical significance of the other genetic changes may involve the overexpression of the antiapoptotic protein bcl-2, together with lower levels of the proapoptotic protein bax. Drugs that are active in treating CLL would appear to reverse the bcl-2/bax ratio.

C. OTHER IMPORTANT LABORATORY STUDIESOther important laboratory studies for diagnosing CLL include serum protein electrophoresis to detect an M protein and provide an overall assessment of immunoglobulin production. CLL patients can present with diffuse hypogammaglobulinemia or will develop hypogammaglobulinemia during the course of their disease. Tests for autoantibodies, including both a Coombs' test and a measurement of platelet-associated immunoglobulin, should be obtained in any patient who presents with anemia or thrombocytopenia. In patients with very large tumor burdens, the serum lactic dehydrogenase (LDH) level, B2-microglobulin, and uric acid levels can be elevated.

Differential DiagnosisMany of the B-cell lymphomas may have a leukemic component with increased numbers of circulating cells. If adenopathy is a prominent aspect of the clinical presentation, a node biopsy is indicated to rule out a more aggressive form of lymphoma. The presence of relatively large amounts of sIg also indicates that the physician is not dealing with typical B-cell CLL. Disorders such as hairy-cell leukemia, prolymphocytic leukemia, and leukemias involving large, less-well differentiated cells are usually easily distinguished on the basis of morphology (Figure 21-2). Mantle cell lymphoma is another B-cell malignancy that expresses CD5 but is distinguished from CLL by the absence of CD23, the presence of larger cells, and by a much more aggressive course. Seventy percent of these cases show a t(11;14) translocation involving the bcl-1 locus, which results in the overexpression of cyclin D1a critical regulator of the cell division cycle.

TherapyStaging systems for CLL have been proposed and are useful in protocol studies and in predicting the prognosis of individual patients. Adverse prognostic factors include a lymphocyte count greater than 300,000/µL, atypical lymphocyte morphology, lymphadenopathy, a short lymphocyte doubling time, trisomy 12 or more than one cytogenetic abnormality, high level expression of CD38 and ZAP-70, and a large tumor burden as indicated by an elevated LDH, B2-microglobulin, or both. Autoimmune anemia or thrombocytopenia and frequency of infections also have a major impact on prognosis.Most patients will have a relatively chronic clinical course, some progressing very slowly and succumbing to unrelated disorders, others progressing more rapidly, succumbing to complications of infection, anemia, thrombocytopenia, or chemotherapy. The disease can also undergo transformation to a much more aggressive form of lymphoma such as diffuse histiocytic lymphoma with massive splenomegaly (Richter syndrome), prolymphocytic leukemia, or, very rarely, acute lymphocytic leukemia or multiple myeloma. One of these should be suspected if the patient's course appears to change abruptly.Although there is no curative therapy, recent advances have led to a substantial number of complete responses and prolonged disease-free survival. In general, treatment is directed toward palliation of symptoms and prolongation of life with minimal morbidity. Patients without symptoms (eg, fever, weight loss, night sweats, fatigue, bulky adenopathy) and without complications such as thrombocytopenia, anemia, or infections should not be treated immediately. Chemotherapy directed entirely at lowering the lymphocyte count will be effective but there is no evidence that it prolongs life or slows progression, and it certainly increases morbidity owing to infection and exposes the patient to the risk of second malignancies.

Drug TherapyWhen treatment is initiated, it should be designed to reduce and control whatever symptoms gave rise to the necessity for treatment. If symptoms are abolished, there is no need to continue treatment. Traditionally, first-line therapy has been chlorambucil, 4–6 mg orally each day for 4–7 days every 3–4 weeks. Higher doses, up to 15 mg/m2/day for 5 days per month, have been used in patients with disseminated disease. This will usually reduce the tumor burden (blood lymphocytosis, node enlargement, and splenomegaly) for many months to years. However, chlorambucil therapy does not extend lifespan; the natural history of CLL is unaffected.Recent studies have shown that fludarabine, a nucleoside analogue, as a single agent is more effective than chlorambucil for initial therapy. It produces a higher rate of complete and partial remissions, and the duration of response is nearly twice that of chlorambucil.

Nevertheless, to date there is no evidence for prolonged survival or cure, and fludarabine has the disadvantages of increased expense, intravenous administration, and a higher incidence of both myelosuppression and immunosuppression. The currently recommended dose of fludarabine is a bolus of 25 mg/m2 intravenously for 5 days each month, continuing to best response plus 2 additional months. When used for more than 4–6 months, T-cell subsets should be monitored to prevent a major reduction in CD4 lymphocytes. In addition, prophylaxis with Bactrim and fluconazole is recommended to prevent opportunistic infections. Autoimmune hemolytic anemia and prolonged thrombocytopenia have both been reported as complications of fludarabine therapy. Combinations of fludarabine (30 mg/m2 daily for 3 days) with Cytoxan (300 mg/m2 daily for 3 days) may give a better response in heavily treated patients. The addition of rituximab, a monoclonal antibody directed against CD20 has provided even higher levels of complete response (up to 77%). In CLL rituximab must be given in higher doses (500 to 2250 mg/m2 weekly) to overcome the presence of circulating soluble CD20. The ability to achieve complete responses with combinations such as these has made it possible to treat young patients with autologous peripheral blood stem cell transplantation, although the results of such treatment are not yet known.Other second-line drugs for patients who fail initial treatment are 2′-chlorodeoxyadenosine (2-CdA) and pentostatin (deoxycoformycin). Like fludarabine, these agents can cause severe immunosuppression. Another alternative is alemtuzumab (Campath-1H), a monoclonal antibody directed against a common lymphocyte antigen (CD52). The use of either rituximab or alemtuzumab is associated with a common “first dose effect†consisting of rigors, �fever, hypotension, and respiratory distress. This syndrome can be severe in as many as 14% of patients receiving alemtuzumab. When a patient's disease transforms into a more aggressive lymphoma, combination chemotherapy is indicated. Symptomatic bulky adenopathy will respond promptly to local radiotherapy.

ComplicationsComplications such as hemolytic anemia and immune thrombocytopenia are treated with corticosteroids in the usual fashion, starting with a high dose of prednisone, 60–90 mg orally daily, and then tapering to a minimal daily or every-other-day maintenance dose. Recurrent infections can be decreased by administering intravenous gamma globulin (400 mg/kg every 3 weeks). Owing to its expense, intravenous gamma globulin should be reserved for patients with severe hypogammaglobulinemia and documented recurrent bacterial (encapsulated organism) infections.T-CELL CLL (CD4 TYPE)

Clinical FeaturesT-cell CLL associated with HTLV-1 is the most common form of CLL in parts of Japan but is rare in Western countries. Although the retrovirus that causes it is closely related to the HIV virus of AIDS, T-cell CLL causes only uncontrolled proliferation of the CD4 T cell rather than its destruction. These viruses use the CD4 molecule as their binding site on the cell, and thus the infection is specific for the CD4 T cell.Outside of Japan, cases of T-cell CLL are not always associated with the same virus. Their incidence appears, however, to be increasing, and it is likely that there are other related retroviruses involved with these disorders. Reports of involvement by defective retroviruses, herpes virus, and Epstein-Barr virus have appeared, but as yet no common element has been identified. T-cell CLL is a less homogeneous disorder than B-cell CLL and has been classified in several different ways. The typical disease seen in Japan has been called adult T-cell leukemia. In the West, it has been called various names depending on the presentation, morphology, and the rate of progression.

The CD4 T-cell leukemias share several clinical characteristics. Most striking is a propensity to involve the skin. The skin disease known as mycosis fungoides is an infiltration of CD4 T cells often associated with a leukemic population of CD4 T cells. When the leukemia is prominent and the cells have a characteristic nuclear morphology (ie, a folded or “cerebriform†nucleus), the disease is known as Sézary syndrome. Many patients with �CD4 T-cell leukemia will have skin involvement ranging from a diffuse erythroderma with exfoliation to patchy plaquelike or nodular infiltration. Infection of the skin lesions is common and is the most common cause of death.T-cell CLLs in general have a more aggressive course, with more adenopathy, more susceptibility to viral infection and opportunistic infection, and a worse overall prognosis. It is difficult to generalize, however, because of the heterogeneity of the disorders. Some cases are as benign as B-cell CLL but others are rapidly progressive.

Laboratory StudiesCD4 T-cell disease is frequently associated with hypergammaglobulinemia, sometimes to a striking degree and often predominantly IgA. It is tempting to associate this with the “helper†nature of the CD4 T cells, but this is probably an oversimplification. Despite the� hypergammaglobulinemia, these patients have poor antibody responses to specific pathogens and have defects in both humoral and cellular immunity. The propensity to autoimmune phenomena seen in B-cell CLL is not observed.Unlike the situation with B-cell CLL, there is no immunologic marker for T cells that indicates clonality. Thus the presence of many CD4 T cells in skin, blood, or nodes cannot be taken as definitive evidence that they are malignant. Since CD4 is the predominant T-cell subtype normally, it is sometimes difficult to be certain whether they are malignant. One useful clue comes from examining several different T-cell–associated markers. Normal mature CD4 T cells also express CD2, CD3, CD5, and CD7. Often, a malignant population will lack one or more of these markers or express them in abnormal amounts, and this may indicate that they are not normal. In addition, normal resting CD4 T cells do not express HLA-DR or CD38. Thus intense expression of these activation markers may indicate that the cells are proliferating abnormally.At present, the only definitive test for clonality among the T cells is to study the rearrangement of the T-cell receptor genes. Most malignant T cells will have a clonal rearrangement of the TCR-β and -γ genes that can be detected either by restriction mapping and Southern blotting or more recently by polymerase chain reaction (PCR).

TherapyBecause of the more aggressive nature of the T-cell CLLs, the relatively passive approach used with B-cell CLL is inappropriate. Treatment aimed at decreasing the cell count, controlling skin involvement, and reducing adenopathy should be undertaken. Cures cannot be achieved with combination chemotherapy, however; thus single-agent treatment is usually employed to achieve specific therapeutic goals.In the early stages of cutaneous T-cell lymphomas, the malignant T cells appear to be dependent on stimulation by epidermal Langerhans cells, and therapy directed entirely to the skin can be highly effective, even though it may be possible to demonstrate malignant T cells in other sites as well. Topical chemotherapeutic agents such as corticosteroids, mechlorethamine, or carmustine can be used on localized lesions. More extensive involvement responds to electron beam irradiation if available. Phototherapy, with oral psoralen with UVA irradiation or ultraviolet (UV) B, is often used as first-line therapy and has the advantage of also treating unrecognized subclinical lesions. Because T cells circulate relatively more than B cells, they sometimes respond to repeated leukapheresis with

decreased skin infiltration and adenopathy as well as decreased cell count. Photopheresis, in which the circulating T cells are exposed to UV radiation in an extracorporeal circuit, can achieve compete remissions, even though only a small fraction of the total T-cell pool is being treated. Systemic chemotherapy with single alkylating agents such as chlorambucil, cyclophosphamide, or BCNU can be beneficial with or without the addition of glucocorticoids. In more aggressive situations, combination chemotherapy including such drugs as methotrexate, bleomycin, and Adriamycin is used. With most treatments, the initial response rate is high (50–70%), but long-term responses are difficult to achieve.T-cell CLL is uniquely susceptible to several newer immunologically oriented therapies that are still being investigated. These include inhibitors of adenosine deaminase such as pentostatin and 2-CdA. In addition, therapy with monoclonal antibodies directed against CD4 or CD52 (Campath-1H) has been effective in rapidly lowering the cell count and sometimes inducing remission. A conjugate of diphtheria toxin with interleukin (IL)-2 (DAB389IL-2) has been recently approved for treatment of patients who have failed other therapies. It is likely that these approaches will become more attractive with further investigation. Attempts at therapies with stem-cell transplantation, interleukin inhibitors, and antibodies conjugated to toxins are being evaluated.

T-CELL CLL (CD8 TYPE)Occasionally, patients with what appears to be a typical T-cell CLL will prove to have not CD4, but CD8-bearing T cells. These cases can be distinguished only by immunologic study and not on any reliable clinical grounds. Sometimes such cases will express both CD4 and CD8, thus reflecting an early stage of T-cell maturation normally found only in the thymus. A unique presentation of CD8 T-cell leukemia, however, appears to be increasing in frequency and is clinically distinct. This type has been given various names, the most common of which are large granular lymphocytic (LGL) leukemia and T γ-lymphocytosis.

Clinical FeaturesLGL leukemia patients may present with lymphocytosis in the same way as other CLLs. However, they usually show only modest lymphocytosis or none at all together with granulocytopenia, aplastic anemia, or pancytopenia. There is evidence that CD8 T cells are capable of directly inhibiting one or more aspects of hematopoiesis and that this gives rise to this unique clinical presentation. In the more common CLLs, hematopoietic failure is not seen until there is extensive marrow infiltration with CLL cells. With LGL leukemia, the offending CD8 T cells may not be present in large numbers. Approximately 25% of these patients will also have preexisting rheumatoid arthritis or other autoimmune disorder.The course of LGL leukemia is highly variable. Some patients appear to have little or no progression of the lymphoproliferative process and may only need to be treated for their anemia or granulocytopenia, whereas others have a more aggressive course resulting in progression to florid lymphoma or lymphocytic leukemia or both.

Laboratory StudiesThe malignant cells (“large granular lymphocytesâ€) resemble “atypical lymphocytesâ€� � of the type sometimes seen in infectious mononucleosis. They are larger than normal lymphocytes, with a more open chromatin pattern and with a few prominent azurophilic granules in their cytoplasm. Marker studies show expression of the normal T-cell lineage markers CD3 and CD8. In addition they typically express CD57 and activation markers such as HLA-DR and CD38. In some cases they have low or absent expression of the CD5 that should be present on normal T cells.

This morphology and phenotype are associated with activated cytotoxic T cells. These cells resemble and are sometimes confused with NK cells because they share some of the morphologic characteristics and markers such as CD57. Gene rearrangement studies have shown definitively, however, that they are conventional T cells. The entity of true NK-cell leukemia is rare. Although morphologically very similar, in these cases the cells do not show rearrangement of T-cell receptor genes and do not express CD3. The presentation is much more acute and the course much more aggressive.

TherapyUp to one-third of patients may require no chemotherapy directed at the lymphoproliferative disease but only supportive therapy for anemia or recurrent infections owing to granulocytopenia. Others respond to single-agent treatment with chlorambucil or cyclophosphamide, with or without prednisone. With transition to more aggressive disease, combination chemotherapy is indicated; however, the response rate is not high in this situation.

HAIRY-CELL LEUKEMIAHairy-cell leukemia (HCL) was named for its unusual morphology. The malignant lymphocytes have very long filamentous cytoplasmic projections that are sometimes difficult to see in dried stained films but are prominent in wet mounts observed by phase microscopy. HCL has also been called “leukemic reticuloendotheliosis,†perhaps because of the �tendency for the malignant cells to infiltrate the marrow, liver, and spleen.

Clinical FeaturesLike many of the CLLs, this disorder occurs most commonly in older adults and frequently has a unique clinical presentation characterized by extensive marrow involvement with pancytopenia and relatively prominent splenomegaly. It is more often seen in males than females (4 to 5:1).

Laboratory StudiesThe cell that originates HCL has been the subject of considerable investigation. Some HCL cases have cells with properties of both lymphocytes and macrophages in that the cells can be mildly phagocytic and sometimes have markers associated with macrophages. Careful marker studies and gene rearrangement studies have shown, however, that they are always either B or T cells, more commonly B cells. It appears that the disease is not derived from some normal “hairy cell†but rather arises in normal B and T cells just as other CLLs. The most useful �markers for these cells, in addition to the usual lineage-specific B-cell markers (CD19, CD20, and sIg), are the absence of CD5, CD10, and CD23 and the strong presence of CD11 and CD103.The initial CBC in the patient with HCL usually shows mild to moderate pancytopenia. The number of abnormal lymphocytes in circulation is not dramatically increased. A careful inspection of the blood film may reveal the classic hairy cell (a small lymphocyte with filamentous projections of cytoplasm; see Color Plate 48). A special stain, the tartrate-resistant acid phosphatase stain (see Color Plate 47), can be used to confirm the presence of hairy cells in circulation. The characteristic staining pattern is one of a polar deposit of brownish-red material surrounded by unstained cytoplasm.The diagnosis of HCL can also be made on the histology of the marrow or spleen. When the marrow is infiltrated by hairy cells, it usually cannot be aspirated. A marrow biopsy specimen will reveal, however, the typical morphologic pattern of the malignant hairy cell. Once again, the tartrate-resistant acid phosphatase stain can be used to confirm the diagnosis.

Occasionally, the diagnosis of HCL is made from liver or spleen tissue obtained by a biopsy or at the time of surgery.

TherapyThe prognosis of HCL is similar to that of most other CLLs. Some cases are quite indolent and require therapy primarily for complications such as infection, anemia, thrombocytopenia, or symptomatic splenomegaly. Other cases are more aggressive with transitions to aggressive lymphomas. In general, therapy should be begun if the patient is symptomatic or if there is clear progression of the disease.HCL appears to be unique among the CLLs because it responds very well to therapy with interferon, with complete or partial response rates of about 80% but no evidence for cure. Even higher complete remission rates and prolonged relapse-free survival are obtained with pentostatin (deoxycoformycin) and with 2-CdA. Fludaribine has shown similar results and has been effective in patients previously treated with other agents.Prior to the use of these drugs, splenectomy was considered the initial therapeutic step owing to a high frequency of apparent remissions after splenectomy. In patients with massive splenomegaly or severe hypersplenism, splenectomy is still the best first-treatment option. If the patient is not a candidate for surgical splenectomy, splenic irradiation is an alternative. When splenomegaly is not pronounced, chemotherapeutic options are available, each of which appears to offer good results. The purine analogues are now preferred to interferon as initial therapy. Overall survival is 80–90% over 5 years for each of the drugs; longer follow-up data are needed to determine if one of the agents can provide substantially longer survival. Patients who relapse or are refractory may respond to rituximab, given in a dose of 375 mg/m2 weekly for 8 weeks.

BIBLIOGRAPHYBartlett NL, Longo DL: T-small lymphocyte disorders. Semin Hematol 1999;36:164.Cheson B et al: National Cancer Institute–sponsored working group guidelines for chronic lymphocytic leukemia: Revised guidelines for diagnosis and treatment. Blood 1996;87:4990.Dhodapkar MV et al: Clinical spectrum of clonal proliferation of T-large granular lymphocytes: A T-cell clonopathy of undetermined significance? Blood 1994;84:1620.Diamandidou E, Cohe PR, Kurzock R: Mycosis fungoides and Sezary syndrome. Blood 1996;88:2385.Flinn IW, Grever MR: Chronic lymphocytic leukemia. Cancer Treat Rev 1996;22:1.Goodman MG et al: New perspectives on the approach to chronic lymphocytic leukemia. Leuk Lymphoma 1996;22:1.Hamblin TJ et al: Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999;94:1848.O'Brien S, del Giglio A, Keating M: Advances in the biology and treatment of B-cell chronic lymphocytic leukemia. Blood 1995;85:307.Rozman C, Montserrat E: Chronic lymphocytic leukemia. N Engl J Med 1995;333:1052.Shanafelt TD, Geyer SM, Kay NE: Prognosis at diagnosis: Integrating molecular biologic insights into clinical practice for patients with CLL. Blood 2004;103:1202.Tallman MS et al: Treatment of hairy cell leukemia: Current views. Semin Hematol 1999;36:155.Thomas DA et al: Rituximab in relapsed or refractory hairy cell leukemia. Blood 2003;102:3906.