Chronic Lymphocytic Leukaemia and Other Leukaemias of Mature B and T Cells

Chronic lymphocytic leukaemia and other leukaemias of mature B and T cells - technical

Essentials

Chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL) is the most prevalent lymphoid neoplasm in Europe and North America, but its cause remains unknown. The ‘cell of origin’ is a mature B lymphocyte that has rearranged its immunoglobulin gene, expresses surface immunoglobulin, and is characterized by defective apoptosis.

Clinical features

Most patients have no clinical features of disease and diagnosis is made incidentally on discovery of lymphocytosis. A few have rapidly progressive disease and develop symptoms from (1) tissue accumulation of lymphocytes—e.g. disfiguring lymphadenopathy, splenomegaly causing abdominal discomfort; or (2) effects of marrow failure cytopenias—e.g. anaemia, thrombocytopenia. Patients also have an increased risk of developing autoimmune cytopenias and of second malignancies.

Diagnosis and clinical staging

Diagnosis is usually made by analysis of the immunophenotype of malignant cells from the blood or (in rare patients without a detectable monoclonal B cell population in the blood) lymphocytes from the bone marrow, lymph nodes or spleen. Current diagnostic criteria have an arbitrary requirement for (1) B-lymphocyte count >5 × 109/litre, or (2) clinically detectable adenopathy—at least 1 cm in diameter, or (3) organomegaly, or (4) over 30% bone marrow involvement by CLL cells. Staging is based on clinical examination and blood count evaluation.

Treatment and prognosis

Treatment—there is no standard curative therapy, and patients should not be treated until they have progressive and symptomatic disease or develop anaemia or thrombocytopenia due to bone marrow failure. If a decision is made to treat, then the best initial treatment is not certain: single-agent therapy with oral chlorambucil was until recently regarded as the standard of care, but (excepting in frail patients) current practice has moved towards regimen such as those employing purine-analogues, cyclophosphamide, and rituximab, although the only potential curative treatment is allogeneic stem cell transplantation.

Prognosis—this is highly variable and depends on the clinical stage of disease, biological characteristics of the malignant cells, and the general health of the patient. Those with advanced stage disease have a median survival of 4 to 6 years.

Introduction

The mature lymphocytic leukaemias were historically defined by light microscopic cell morphology and included a wide range of diseases derived from different classes of lymphocytes. In recent years there have been major improvements and advances in the understanding of lymphocyte biology resulting in the development of better diagnostic methodologies which are now routinely used in more accurate diagnosis, clinical management decisions, and subsequent follow-up. Individual diseases can now be defined and diagnosed at both a cellular and molecular level. Most patients with mature lymphocytic leukaemias in Europe and North America have chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL). The other less frequently encountered entities, which also need to be considered in the differential diagnosis of CLL, include the leukaemic phase of B-, T-, and natural killer (NK)-cell lymphomas, prolymphocytic leukaemias, and the nonclassified chronic lymphoproliferative disorders. This chapter concentrates on CLL, with only limited reference to the rarer malignancies of mature lymphocytes.

CLL, the most prevalent lymphoid neoplasm in Europe and North America, is a distinct B-cell malignancy. The disease has a protean clinical presentation, marked variation in the rate of disease progression, and an increasing number of new treatment options which have become available over the past 2 decades. The challenge to the medical practitioner is still to make an accurate diagnosis, recognize the significance of newer prognostic factors and the indications for treatment, and to be aware of and know how to manage the many potential complications of the disease. Although CLL is incurable with standard therapy and will eventually cause major morbidity and mortality in most patients who have the disease, good medical care can improve the quality of life and increase longevity for many patients with the disease.

Historical perspective

The leukaemias of mature lymphocytes were first recognized in the latter half of the 19th century. The subsequent recognition of the pivotal role of lymphocytes in the immune system led to the discovery and recognition of the different T, B, and NK subsets. This information has now been combined with a better understanding of lymphocyte biology to develop newer classifications of lymphoid malignancies—those of the Revised European-American Classification of Lymphoid Neoplasms (REAL) and the World Health Organization (WHO)—based on the presumptive normal counterpart of the malignant cells. CLL and the other leukaemias of mature lymphocytes with similar light microscopic cellular morphology are now recognized to be different diseases.

The clinical presentation of CLL has changed dramatically in the past few decades. The widespread use of automated cell counters providing rapid and accurate blood lymphocyte counts has greatly increased the incidental finding of lymphocytosis. In these patients, lymphocytes can be characterized on the flow cytometers in clinical pathology laboratories. This often results in a diagnosis of CLL. Among populations with access to these technologies, most CLL patients are thus now diagnosed early with asymptomatic disease. Presentation with symptomatic disease is indeed becoming less common.

CLL and small lymphocytic lymphoma (SLL) were previously considered to be different diseases. However, the recognition that CLL/SLL cells have the same immunophenotype with considerable overlap in presentation and progression, has led to inclusion of both of them in the CLL category in the REAL and WHO classifications. Clinical presentation of the disease with predominance of adenopathy vs high circulating numbers of leukaemic cells is likely to reflect differences in CLL cell trafficking and does not appear to have any major biological or clinical importance.

In the last 3 decades there has been a marked improvement in the treatment options available for patients with progressive CLL. Single-agent alkylator therapy has been supplemented with purine analogues and more recently lymphocyte-targeting monoclonal antibodies. Combinations of these therapies (chemoimmunotherapy (CIT)) have resulted in better and more durable responses to therapy, which are associated with longer disease-free periods and a subsequent improvement of the quality of life for these patients.

Aetiology, genetics, pathogenesis, and pathology

The aetiology of CLL remains essentially unknown. CLL is a familial disease in about 10% of patients who have a first-degree relative with CLL or another B-cell lymphoproliferative disorder (LPD). Additional evidence for a genetic predisposition for CLL is the marked ethnic variation in the incidence of the disease, which remains relatively unchanged after large population migrations. The highest rates of CLL are in patients of European descent, with a substantially lower risk in people of South-East Asian ancestry. The specific genetic defects in susceptible patients have not yet been clearly defined,

The role of environmental factors in the aetiology of CLL is poorly understood. Epidemiological studies raise concerns about the increased risk in patients with exposure to industrial and agricultural chemicals. Although CLL was previously not considered to be induced by radiation, more recent studies suggest that radiation exposure could increase the risk. The most compelling evidence for a possible environmental agent in the aetiology of CLL comes from recent studies of the variable region allele use in the immunoglobulin molecule expressed by CLL cells. These show a restricted gene usage and limited stereotypes which suggest a possible aetiological role for as-yet-undefined environmental or endogenous antigens. The ongoing study of the aetiology of CLL could be informative in eventually directing preventative measures.

The current model of B-cell lymphoid malignancies assumes that distinct diseases evolve from malignant transformation of lymphocytes at a specific stage of maturation. However, the ‘cell of origin’ of CLL is not yet fully defined. The culprit cell is a mature B lymphocyte that has rearranged its immunoglobulin gene and does express surface immunoglobulin. However, somatic hypermutation, the result of antigen-driven mutations in the germinal centre of the lymph node, occurs in only about 50% of cases of CLL, while the remaining cases are unmutated. Because somatic hypermutation is considered the basic hallmark of the passage of B lymphocytes through the germinal centre after antigen exposure, this discrepancy does limit the currently ability to determine the cell of origin of CLL. The difficulty relating to the classification of the cell of origin of CLL is exacerbated by the expression of CD5 by CLL cells. CD5 is expressed by most T lymphocytes but only a small subset of normal B cells which produce low-affinity autoreactive antibodies and generally do not undergo maturation in the germinal centre. The relationship between CLL and the normal CD5+ B-cell population is still unclear.

CLL cells are characterized by defective apoptosis which is a major mechanism in this disease. However, the fundamental defect in apoptosis is as yet undefined. CLL cells have disrupted BCL2 gene family expression with higher levels of antiapoptotic genes and lower levels of proapoptotic genes. The mechanism of increased BCL2 expression is unknown, and translocations involving the BCL2 gene are rare. CLL cells are characterized by several recurrent genetic defects which usually occur in subclones of the neoplastic cell population and are considered to be the result of clonal evolution. Of these, deletions of chromosome band 17p13 (loss of p53) and 11q22 (loss of ATM), could indeed impair the activity of an important cell control mechanism. The most common recurrent chromosomal defect is the deletion of 13q14 which results in the loss of the microRNA genes miR15 and miR16, which could play a role in pathogenesis or progression of the disease. Recent studies of CLL cell kinetics using labelling with heavy water have shown that CLL cell turnover is higher than previously measured by less sensitive markers of cell proliferation. These studies showed that daily turnover of cells is in the range of 0.1 to 1%, which suggests a dynamic clone and relatively short CLL cell survival in some patients.

CLL cells are identified by immunophenotyping of membrane proteins. The lymphocytes are examined for expression of CD19 (pan-B-cell marker), light chain restriction (predominant expression of either the κ or λ immunoglobulin light chains), and coexpression of CD5, CD23, dim CD20, and dim expression of surface immunoglobulin/CD79b. These CLL cells usually accumulate in the bone marrow, lymph nodes, and spleen, and traffic between these sites in the blood and lymphatics. CLL cells are often found in viscera, serosal fluids, and cerebrospinal fluid even in early-stage CLL and can infiltrate any site of inflammation.

Pathological effects of CLL cells can be direct and indirect. The most common direct effects of accumulation of CLL cells are lymphadenopathy, splenomegaly, hepatomegaly, and bone marrow failure. Lymphadenopathy is an earlier event in disease progression followed by splenomegaly and hepatomegaly, and bone marrow involvement resulting in cytopenia is usually a late event. In contrast, the indirect effects of CLL are less predictable, and their mechanism is not well understood. Patients with CLL have an early-onset defect in humoural immunity characterized by decreased antibody levels and increased rates of infection with encapsulated organisms. T-cell function is usually well preserved in early-stage disease despite a skewed T-cell repertoire. Patients also have an increased risk (∼5%) of developing autoimmune cytopenias during the course of their disease. These can present as autoimmune hemolytic anaemia (AIHA), immune thrombocytopenia (ITP), pure red blood cell aplasia (PRCA), or rarely autoimmune granulocytopenia. In addition, CLL is also associated with an increased risk of developing second malignancies. The most common second haematological malignancy is diffuse large cell lymphoma (Richter’s transformation) which is often, but not always, clonally related to the CLL. The most common nonhaematological malignancies are squamous and basal cell carcinomas, which can be aggressive. Lung cancer risk is markedly increased in smokers with CLL, while the risk of most other common cancers is also increased. The reason for the increased risk of second malignancies is unknown, but contributing factors could include a genetic predisposition, immunosuppression, and shared environmental risk factors.

Epidemiology

CLL is the most prevalent lymphoid malignancy in Europe and North America, with a lower prevalence in Africa and lowest prevalence in the Far East. In most patients with access to modern medical care, CLL is an incidental diagnosis made during investigation of lymphocytosis. These patients usually have early-stage asymptomatic disease.

CLL is very rare in patients under the age of 30, and the median age at diagnosis is about 70 years. There is a 1.5 to 2:1 male to female predominance. Most patients with CLL will die of the disease or its complications. CLL is likely to decrease the overall survival of all patients who have the disease, even older patients with early-stage disease.

The improvement in diagnostic methods has resulted in an increased recognition of small monoclonal B-cell populations, often with a CLL immunophenotype, in patients with normal lymphocyte counts and no other evidence of CLL. This monoclonal B-cell lymphocytosis (MBL) increases in prevalence with age and can be detected in over 3% of Europeans over the age of 65 years. The natural history of MBL is not yet defined, but retrospective data suggest that only a minority of people will progress to CLL or other clinically relevant lymphoid malignancies.

Prevention

There are no known preventive measures to decrease the risk of CLL.

Clinical features

CLL has a highly variable clinical presentation and course. Most patients now have an incidental diagnosis on investigation of lymphocytosis with no clinical features of disease. These patients should have as complete an evaluation of the prognostic biological characteristics of their disease as possible. Although no treatment is indicated outside of clinical trials, this information is still very important for the planning of subsequent care and to allow the patients to adjust to their new diagnosis.

The clinical manifestations of CLL can be a direct consequence of the disease burden or the indirect effects of the CLL cells. The rate of progression of CLL is highly variable. A minority of patients have rapidly progressive disease and require treatment for symptoms or cytopenia within a few years of treatment. In contrast, about 20 to 30% of patients never need treatment for their CLL. Progressive adenopathy can cause disfigurement and abdominal distention and discomfort. Obstructions of the ureters or other viscera are rare but serious complications when encountered. Progressive splenomegaly can cause abdominal discomfort in the left upper quadrant, abdominal distention, and early satiety. Splenic infarcts can cause severe abdominal pain. Anaemia is usually the first manifestation of bone marrow failure caused by progressive infiltration by CLL cells. This is often followed by the development of thrombocytopenia. However, the differential diagnosis of both anaemia and thrombocytopenia in patients with cytopenia includes AIHA, ITP, PRCA, and other unrelated causes. The lymphocyte count can increase to very high levels in patients with CLL, but complications of even extreme lymphocytosis are extremely rare. In patients with progressive disease, increased tumour burden can be associated with severe fatigue, drenching night sweats, fevers, and nondeliberate weight loss. These clinical features need to be carefully investigated to ensure that they are caused by CLL rather than other medical conditions.

Disruption of immune function by CLL causes both immunosuppression and an increase in autoimmune cytopenia. Because of the early suppression of humoural immunity, patients are at high risk of infections by encapsulated bacteria which can cause severe infections. Further deterioration of immune function including T-cell-mediated immunity will increase the risk of viral reactivation and opportunistic infections as the disease progresses or is treated with therapies that decrease immune function. Autoimmune complications of CLL usually cause cytopenia. The most common problems are AIHA and PRCA resulting in symptomatic anaemia and ITP which can cause bleeding. These abnormalities need to be carefully differentiated from cytopenia caused by bone marrow failure, which has a poorer prognosis and often requires different therapy.

Second malignancies are markedly increased in patients with CLL. CLL is associated with a significant increase in second lymphoid malignancies. The most common of these is diffuse large cell lymphoma which can cause dramatic weight loss, drenching night sweats, fevers, and rapid increases in the size of lymph nodes. Patients with CLL also have an increased risk of developing other second lymphomas including Hodgkin’s lymphoma. CLL is also associated with a significant increase in the risk of nonhaematological malignancies. One of the most common is skin cancer, which can be locally aggressive and metastasize. There is also a substantial additional increase in the risk of lung cancer in smokers with CLL.

Differential diagnosis

The differential diagnosis of CLL depends on the presentation. Most patients present with sustained lymphocytosis. The differential diagnosis then includes benign aetiologies associated with lymphocytosis, which is some times atypical, and other lymphoid malignacies in leukaemic phase. Benign lymphocytosis is usually caused by chronic infections (e.g. hepatitis C). The other lymphoid malignancies that most often present with lymphocytosis with mature small lymphocytes are the leukaemic phase of mantle cell, marginal zone, follicular, and lymphoplasmacytic lymphoma, hairy cell leukaemia, prolymphocytic leukaemia, and the unclassified chronic B-cell lymphoproliferative disorders. In patients presenting with lymphadenopathy and splenomegaly, the differential diagnosis includes a wide range of benign and malignant causes, and when malignant blood lymphocytes are not available for analysis, a bone marrow or lymph node biopsy, or even splenectomy could be required to establish the diagnosis.

Clinical investigation

CLL is most easily diagnosed by analysis of the immunophenotype of malignant cells from the blood. In rare patients without a detectable monoclonal B-cell population in the blood, lymphocytes from the bone marrow, lymph nodes, or spleen can be examined. Staging is based on a clinical examination and blood count evaluation and does not require imaging studies or a bone marrow study (Bullet list 1). Bone marrow studies are required to investigate the cause of cytopenias and are done prior to initiation of therapy by many physicians to ensure that patients do not have other causes of cytopenia and to determine tumour burden. Imaging studies are not required routinely in all patients, and their use can be limited to investigating specific concerns. However, an increasing number of treating physicians do CT scans before starting specific therapy as a baseline study to facilitate evaluation of the therapeutic outcome. These studies could be useful in planning subsequent management especially in younger patients with CLL. Testing for prognostic factors is important and is detailed in the section on staging CLL.

Criteria for diagnosis

The CLL cell typically coexpresses the B-cell surface antigen CD19 with CD5 and CD23 and has low levels of expression of surface immunoglobulin (and CD79b) and CD20. These characteristics are used for diagnosis by flow cytometric or immunohistochemical techniques. Interphase fluorescent in situ hybridization (FISH) examination of CLL cells with an IGH probe is very useful for excluding mantle cell lymphoma with its characteristic t(11;14). The current criteria for diagnosis of CLL have an arbitrary requirement for a B-cell lymphocytosis >5 × 109/litre, clinically detectable adenopathy (at least 1 cm in diameter), organomegaly, or >30% bone marrow involvement by CLL cells.

Staging CLL

The clinical staging systems for CLL are based on readily available clinical data. The widely used Rai and Binet classifications use clinical examination and the complete blood count to determine tumour burden (Bullet list 1). These simple methods are very effective at identifying patients with advanced-stage disease who have a poorer prognosis (median survival of about 4–6 years). However, clinical staging using the Rai or Binet classifications does not provide any information on the risk of disease progression in the majority of patients who are diagnosed with early-intermediate-stage CLL.

Improvements in the diagnosis and management of CLL in the past few decades have increased the utility of determining prognosis at diagnosis in earlier-stage disease. This information can be very useful to health care providers and patients in planning medical care. There has been impressive progress in defining molecular determinants of risk in CLL patients. These are direct measurements of critical biological parameters in the malignant CLL B cells rather than indirect measures of tumour progression. The best-studied novel parameters are immunoglobulin mutation sequence analysis (mutation status of IgVH), specific chromosomal defects detected by using interphase FISH, expression of the intracellular protein ZAP-70, and membrane protein CD38 (Table 1). IgVH mutation (≥2% difference from germline sequence) is associated with a significantly better survival in multiple retrospective analyses. FISH analysis is currently the most useful available clinical method of chromosome analysis in CLL and usually includes probes for detection of deletions at chromosome bands 13q14, 11q22, 17p13, and 6q21, trisomy 12 (12+), and abnormalities involving 14q32 (IgH locus). Deletion of 17q13 (17p13-) resulting in loss of p53 is associated with a shorter time to initial treatment, poor response to treatment, and very poor survival. Deletion of 11q22 (11q22-), resulting in loss of the ATM gene, is more common in younger patients and associated with more aggressive disease, bulky adenopathy, and a poorer prognosis. Patients with 12+ or no detected abnormality have an intermediate prognosis and patients with only deletion of 13q14 (13q14-) have the most favourable prognosis of all. ZAP-70 is an intracellular signalling molecule expressed at a high level by T lymphocytes but only in a small minority of normal B cells. ZAP-70 expression (≥20% positive cells) was originally predicted to be a surrogate marker for unmutated IgVH. Although this predictive capability of ZAP-70 measurement was subsequently found to be limited, ZAP-70 expression is an independent marker of poor prognosis in CLL. Unfortunately, the assay for ZAP-70 expression is technically demanding and poorly reproducible, which limits its clinical application. CD38 is a cell membrane protein of uncertain function expressed by mature B cells and plasma cells. Expression of CD38 by ≥30% of CLL cells is an independent predictor of poor prognosis, but the expression of CD38 can change during the course of CLL, and there is still no consensus on the clinical application of this measurement. Additional biological markers of prognosis in early-stage CLL include serum β2-microglobulin, soluble CD23, thymidine kinase, and the percentage of smudge cells on the peripheral smear (low numbers predict for poorer prognosis). The challenge is to combine a selection of these factors and other markers of prognosis into a practical prognostic formulation that will be easy to use and accessible to most patients with CLL.

Bullet list 1 Clinical staging of CLL

Rai classification
  • 0 lymphocytosis
  • I lymphocytosis and lymphadenopathy
  • II lymphocytosis and palpable liver or spleen enlargement
  • III lymphocytosis and anaemia (Hgb <110 g/litre)
  • IV lymphocytosis and thrombocytopenia (platelets <100 × 109/litre)
Modified Rai classification
  • Low risk stage 0
  • Intermediate risk stages I–II
  • High risk stages III–IV
Binet classification
  • A lymphocytosis and lymphadenopathy in <3 areasa
  • B lymphocytosis and lymphadenopathy ≥3 areasa
  • C anaemia (<100 g/litre) and/or thrombocytopenia (<100 × 109/litre)

a - Areas are cervical, axillary, and inguinal nodes (unilateral or bilateral), liver, and spleen (n = 5).

Table 1 Molecular prognostic factors and risk of disease progression in early-stage CLL
  Low risk Intermediate risk High risk
FISH 13q14- as sole abnormality Nil, 12+ 17p13-, 11q22-
IgVH mutation Mutated (≥2%) except for VH3-21 Unmutated VH3-21 mutated  
ZAP-70 (≥20%) Negative Positive  
CD38 (≥30%) Negative Positive  

FISH, fluorescent in situ hybridization.

Treatment

Currently, there is no standard curative therapy for CLL. Patients should not be treated until they have progressive and symptomatic disease or develop anaemia or thrombocytopenia due to bone marrow failure. In this regard, early treatment of all patients has not been shown to be of benefit and could even be detrimental to some patients.

Initial treatment

Patients are treated for progressive disease as defined by the National Cancer Center Working Group criteria of 1996 which were recently revised by the International Workshop for CLL (IWCLL). These recommend that patients should be treated only if they are symptomatic from progressive disease (severe fatigue, drenching night sweats, fever, >10% weight loss, discomfort from lymphadenopathy or splenomegaly), or if they develop anaemia (hemoglobin <11 g/dl) or thrombocytopenia (platelets <100 × 109/litre).

The best initial treatment for CLL is not yet defined and is likely to differ depending on the biology of the disease, patient comorbidities, and functional status of the patient. Single-agent therapy with oral chlorambucil was until recently regarded as the standard of care and still could have a role for initial treatment of frail patients or those with multiple comorbidities. The purine analogues (fludarabine, pentostatin, and cladribine) in use since the late 1980s, have achieved higher response rates than chlorambucil, but improvements in overall survival have been difficult to prove largely because of crossover of relapsing patients to other effective therapies. The German, British, and American trials have shown that results with a combination of fludarabine and cyclophosphamide are better than fludarabine alone. Therapy of CLL has been further improved by the introduction of the therapeutic monoclonal antibodies alemtuzumab (anti-CD52) and rituximab (anti-CD20). However, rituximab has limited efficacy as a single agent, and neither antibody is effective against bulky adenopathy or splenomegaly. Response rates for first-line therapy of CLL are currently highest with the use of chemoimmunotherapy using a combination of purine analogues, cyclophosphamide, and rituximab. The regimen with one of the highest response rates is fludarabine, cyclophosphamide, and rituximab (FCR), but its use is limited by myelotoxicity and infection, and the pentostatin, cyclophosphamide, and rituximab (PCR) regimen seems to be better tolerated. These regimens usually have a high response rate (c.90%) with a complete response rate ranging from 40 to 60%. The median duration of response is about 3 to 4 years. The initial reports of the large German CLL Group prospective randomized trial comparing initial treatment of progressive CLL with FCR vs FC show significantly better survival for those patients treated with FCR. Patients with the 17p13-, who generally have aggressive disease, are very often not responsive to purine analogue–based therapies but do usually respond to regimens employing alemtuzumab.

Relapsed/refractory disease

Patients with progressive disease usually do not need treatment until they once again fulfil the criteria for treatment. There is no standard therapy for this group of patients, and in those who have had an initial duration of response to their first-line treatment of at least 1 year, retreatment with the same regimen is reasonable and recommended by most physicians. In patients with initial treatment failure or earlier progression, treatment options depend on comorbidity and the biological characteristics of the CLL. Treatment options then include alemtuzumab-containing regimens or high-dose corticosteroids. There are an increasing number of drugs showing therapeutic value in these patients, including lenalidomide, flavopiridol, and the newer monoclonal antibodies such as ofatumumab. In patients with extensive comorbidity, treatment could be limited to palliative measures.

High-dose chemotherapy with autologous stem cell support has limited value in CLL. In contrast, allogeneic transplant can induce a therapeutic graft-vs-leukaemia effect and can potentially be curative in CLL. Myeloablative allogeneic transplantation is however associated with very high treatment-related mortality (c.30–40%) largely due to infection, and is thus of limited value. However, reduced intensity conditioning allogeneic transplantation appears to have a lower initial morbidity and mortality and could be an acceptable and reasonable alternative for some patients with aggressive CLL. Use of reduced intensity conditioning regimens requires a pretransplant regimen that can effectively decrease tumour bulk so that the transplanted immune system has sufficient time to develop a therapeutic graft-vs-leukaemia effect. Graft-vs-host disease is often delayed but can be severe and together with donor availability and cost are the major limitations to use of this treatment.

Management of complications of CLL

Autoimmune cytopenia is responsible for about 20% of anaemia and thrombocytopenia in patients with CLL. In CLL patients without a large CLL tumour burden, treatment should be directed at the autoimmune cytopenia. Initial management of severe anaemia or thrombocytopenia is usually corticosteroids but may also require the use of intravenous immunoglobulin (IVIG). Patients with ITP can benefit from splenectomy, but patients with AIHA are less likely to benefit from this measure. Many patients with AIHA and ITP will benefit from the use of rituximab. However, because about half of the cases of PRBCA involve a cellular immunity–mediated mechanism, rituximab is less likely to be effective treatment for this entity. Management of more advanced stage CLL complicated by autoimmune cytopenia requires regimens that can treat both the autoimmune disorder and the CLL. Purine analogue monotherapy can cause autoimmune complications and should be avoided. Effective regimens combine alkylating agents, corticosteroids, and rituximab. The use of purine analogue–containing regimens including rituximab and alkylating agents is controversial.

Infection is the most common direct cause of death in CLL. Even in early-stage CLL, patients have increased susceptibility to infections with encapsulated bacteria which can progress rapidly and prove fatal. CLL patients are also at increased risk of sinusitis and other respiratory tract infections. Patients should be educated about this risk and advised to seek early medical evaluation for all febrile illnesses. With disease progression and treatment, patients develop more severe defects in cellular immunity and become more susceptible to viral and opportunistic infections. Once again, patients need to be educated about the need for early antimicrobial treatment. Prophylactic treatment of patients with monthly IVIG does decrease the risk of bacterial infection but has not been shown to improve overall survival and is expensive and tedious. Use of prophylactic antiviral therapy in patients with recurrent herpes zoster and herpes simplex infections can be beneficial. Vaccination for influenza and pneumococcus are less effective than in immunocompetent subjects but are still useful and indicated.

Second malignancies

Patients with CLL require careful observation for second malignancies. This includes education about the symptoms of transformation including drenching night sweats, fever, and involuntary weight loss. Diffuse large B-cell lymphoma (Richter’s transformation) or Hodgkin’s lymphoma requires immediate treatment, but responses are usually poorer than those achieved by patients with primary lymphoma. CLL patients also need to be educated about skin care including avoidance of sun damage. They need careful observation for the development of skin cancers which should be treated aggressively when detected. An important measure to decrease the risk of other secondary cancers is the cessation of smoking. Careful routine checks for malignancy should be advised and can be beneficial.

Quality of life

A diagnosis of incurable CLL is stressful. This emotional burden is exacerbated by the absence of effective early intervention and the ‘watch and wait’ period of care. Management of this problem can be difficult. Measures of value in alleviating this problem include education, a simple and frank discussion of the disease and its complications, and acceptance of the validity of the patient’s concerns.

Prognosis

The prognosis of patients with CLL is highly variable and depends on the clinical stage of disease, biological characteristics of the malignant cells, and the general health of the patient. Patients with advanced-stage disease have a poor prognosis with a median survival of 4 to 6 years. In contrast, patients with early-stage disease have a wide variation of median survival. This ranges from decades in the lowest risk cohort (mutated IgVH, 13q14- as the sole abnormality on FISH analysis, negative for ZAP-70 and CD38) to a few years for patients with 17p13-.

Areas of uncertainty or controversy

Biology

The cause of CLL and the role of genetic susceptibility to the disease are topics of active research. One of the most interesting aspects is the role of the B-cell receptor and its antigen specificity in the aetiology and progression of CLL

Prognostic markers

The ability to use molecular markers to predict prognosis at diagnosis could be very helpful in the management of patients with CLL. However, the best practical way to combine these tests in clinical practice is still being evaluated.

Treatment

The standard of care is still to treat patients with CLL only when they have progressive disease causing clinical problems. However the ability to predict which patients are at high risk of disease progression could change this paradigm. Selection of a subgroup of patients with lower tumour burden for earlier treatment could in principle be more effective. In addition, the best use of currently available drugs is still undecided. Some of the most effective drugs such as the purine analogues and alemtuzumab are highly immunosuppressive, and the timing and optimal combination of therapy for treatment of each stage of CLL has not yet been defined.

Likely developments over the next 5 to 10 years

Biology

Current research will no doubt result in an improved understanding of the aetiology of the disease including the genetic defects contributing to CLL aetiology. Definition of the immune defects in patients with CLL could result in a much better understanding of the early defect in humoural immunity and help to explain why some patients develop autoimmune cytopenia.

Treatment

Risk-stratified approaches should provide optimal therapies for patients while potentially curative therapies could be developed from attempts to generate the graft-vs-leukaemia effect without transplantation.