CHRONIC LYMPHOCYTIC LEUKEMIA

Introduction
Background

Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is a monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes. It is the most common form of leukemia found in adults in Western countries.1 See histologic sample in the image below.

Peripheral smear from a patient with chronic lymp...
Peripheral smear from a patient with chronic lymphocytic leukemia, small lymphocytic variety.

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Peripheral smear from a patient with chronic lymp...

Peripheral smear from a patient with chronic lymphocytic leukemia, small lymphocytic variety.

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Pathophysiology

The cells of origin in the majority of patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) are clonal B cells arrested in the B-cell differentiation pathway, intermediate between pre-B cells and mature B cells. Morphologically in the peripheral blood, these cells resemble mature lymphocytes.

B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) lymphocytes typically show B-cell surface antigens, as demonstrated by CD19, CD20, CD21, and CD23 monoclonal antibodies. In addition, they express CD5, which is more typically found on T cells. Because normal CD5+ B cells are present in the mantle zone (MZ) of lymphoid follicles, B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is most likely a malignancy of an MZ-based subpopulation of anergic self-reactive cells devoted to the production of polyreactive natural autoantibodies.

B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) cells express extremely low levels of surface membrane immunoglobulin, most often immunoglobulin M (IgM) or IgM/IgD and IgD. Additionally, they also express extremely low levels of a single immunoglobulin light chain (kappa or lambda).

An abnormal karyotype is observed in the majority of patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). The most common abnormality is deletion of 13q, which occurs in more than 50% of patients. Individuals showing 13q14 abnormalities have a relatively benign disease that usually manifests as stable or slowly progressive isolated lymphocytosis.

The presence of trisomy 12, which is observed in 15% of patients, is associated with atypical morphology and progressive disease. Deletion in the short arm of chromosome 17 has been associated with rapid progression, short remission, and decreased overall survival in chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). 17p13 deletions are associated with loss of function of the tumor suppressor gene p53. Deletions of bands 11q22-q23, observed in 19% of patients, are associated with extensive lymph node involvement, aggressive disease, and shorter survival.

More sensitive techniques have demonstrated abnormalities of chromosome 12. Forty to 50% of patients demonstrate no chromosomal abnormalities on conventional cytogenetic studies. However, 80% of patients will have abnormalities detectable by fluorescence in situ hybridization (FISH). Approximately 2-5% of patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) exhibit a T-cell phenotype.

Studies have demonstrated that the protooncogene bcl2 is overexpressed in B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).2 The protooncogene bcl2 is a known suppressor of apoptosis (programmed cell death), resulting in a long life for the involved cells. Despite the frequent overexpression of bcl-2 protein, genetic translocations that are known to result in the overexpression of bcl2, such as t(14;18), are not found in patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).

Studies have shown that this upregulation in bcl2 is related to deletions of band 13q14. Two genes, named miRNA15a and miRNA16-1, are located at 13q14 and have been shown to encode not for proteins, but rather for a regulatory RNA called microRNA (miRNA).3,4 These miRNA genes belong to a family of highly conserved noncoding genes throughout the genome whose transcripts inhibit gene expression by causing degradation of mRNA or by blocking transcription of mRNA. Deletions of miRNA15a and miRNA16-1 lead to overexpression of bcl2 through loss of downregulating miRNAs. Genetic analyses have demonstrated deletion or downregulation of these miRNA genes in 70% of cases of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).

Investigations have also identified a number of high-risk genetic features and markers that include germline immunoglobulin variable heavy chain (IgVH), IgVH V3-21 gene usage, increased CD38 expression, increased Zap70 expression, elevated serum beta-2-microglobulin levels, increased serum thymidine kinase activity, short lymphocyte doubling time (<6 mo), and increased serum levels of soluble CD23. These features have been associated with rapid progression, short remission, resistance to treatment, and shortened overall survival in patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). Germline IgVH has been shown to indicate a poor prognosis. Studies have shown that these patients also have earlier progression of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) after treatment with chemotherapy. The use of certain IgV H genes, V3-21, have also been associated with poor prognosis regardless of IgV H mutational status. Zeta-associated peptide of 70 kilodaltons (Zap70) is a cytoplasmic tyrosine kinase whose expression has been associated with a poor prognosis. Cells with germline IgV H often have an increased expression of Zap70; however, studies have shown discordance rates of 10-20% between IgV H mutational status and Zap70 expression levels. Elevated levels of Zap70 are believed to decrease the threshold for signaling through bcl2, thereby facilitating the antiapoptotic effects of bcl2. Zap70 function also appears to be dependent on heat shock protein 90 (hsp90), whose inhibition may provide a future therapeutic option. Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) should also be distinguished from prolymphocytic leukemia, in which more than 65% of the cells are morphologically less mature prolymphocytes. Frequency United States More than 17,000 new cases of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) are reported every year. The true incidence in the US is unknown and is likely higher, as estimates of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) incidence come from tumor registries, and many cases are not reported. One case series had the actual incidence at 38% higher than estimated from tumor registries. International Unlike the incidence of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) in Western countries, which is similar to that of the United States, chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is extremely rare in Asian countries (ie, China, Japan), where it is estimated to comprise only 10% of all leukemias. However, underreporting and incomplete registry may significantly underestimate the true incidence of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) in these countries. Mortality/Morbidity The natural history of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is heterogeneous. Some patients die rapidly, within 2-3 years of diagnosis, because of complications from chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). Most patients live 5-10 years, with an initial course that is relatively benign but followed by a terminal, progressive, and resistant phase lasting 1-2 years. During the later phase, morbidity is considerable, both from the disease and from complications of therapy.5,6 Race The incidence of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is higher among whites compared with blacks. Sex The incidence of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is higher in males than in females, with a male-to-female ratio of 1.7:1. Age Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is a disease that primarily affects elderly individuals, with the majority of cases reported in individuals older than 55 years. The incidence continues to rise in those older than 55 years. However, there are reports that individuals aged 35 years or younger are being diagnosed with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) more frequently. Clinical History Patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) present with a wide range of symptoms and signs at presentation. Onset is insidious, and it is not unusual for chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) to be discovered incidentally after a blood cell count is performed for another reason; 25-50% of patients will be asymptomatic at time of presentation. Symptoms and signs of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) may include the following: * A predisposition to repeated infections such as pneumonia, herpes simplex labialis, and herpes zoster may be noted. * Enlarged lymph nodes are the most common presenting symptom, seen in 87% of patients symptomatic at time of diagnosis. * Early satiety and/or abdominal discomfort may be related to an enlarged spleen. * Mucocutaneous bleeding and/or petechiae may be due to thrombocytopenia. * Tiredness and fatigue may be present secondary to anemia. * Fevers, chills, and night sweats and weight loss constitute B symptoms seen in chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). * Ten percent of patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) will present with an autoimmune hemolytic anemia. Physical Localized or generalized lymphadenopathy (80-90% of cases) includes the following: * Splenomegaly (30-54% of cases) * Hepatomegaly (10-20% of cases) * Petechiae * Pallor Causes As in the case of most malignancies, the exact cause of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is uncertain. The protooncogene bcl2 is known to be overexpressed, which leads to suppression of apoptosis (programmed cell death) in the affected lymphoid cells. In the majority of cases, this appears to be secondary to alterations in the expression of the miRNAs MIRN15a and MIRN16-1. Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is an acquired disorder, and reports of truly familial cases are exceedingly rareDifferential Diagnoses Acute Lymphoblastic Leukemia Lymphoma, Mantle Cell Acute Myelogenous Leukemia Lymphoma, Non-Hodgkin Chronic Myelogenous Leukemia Myelodysplastic Syndrome Hairy Cell Leukemia Myeloproliferative Disease Lymphoma, Diffuse Large Cell Lymphoma, Follicular Lymphoma, Lymphoblastic Other Problems to Be Considered Hyperreactive malaria splenomegaly Prolymphocytic leukemia Splenic lymphoma with villous lymphocytes Workup Laboratory Studies In patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL), the complete blood cell (CBC) counts with differentials show absolute lymphocytosis with more than 5000 B-lymphocytes/µL for longer than 3 months. Clonality must be confirmed by flow cytometry. The presence of a cytopenia caused by clonal bone marrow involvement makes the diagnosis of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) regardless of the peripheral B-lymphocyte count. Patients with less than 5000 B-lymphocytes/µL with lymphadenopathy and without cytopenias more likely have small lymphocytic lymphoma (SLL), although diagnosis should be confirmed by lymph node biopsy. Patients with a clonal B-cell population less than 5000/µL without lymphadenopathy or organomegaly, cytopenia, or other disease-related symptoms have monoclonal B-lymphocytosis (MBL). MBL will progress to chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) at a rate of 1-2% per year. Microscopic examination of the peripheral blood smear is indicated to confirm lymphocytosis. It usually shows the presence of smudge cells, depicted in the image below, which are artifacts due to damaged lymphocytes during the slide preparation. Peripheral smear from a patient with chronic lymp... Peripheral smear from a patient with chronic lymphocytic leukemia, large lymphocytic variety. Smudge cells are also observed; smudge cells are the artifacts produced by the lymphocytes damaged during the slide preparation. [ CLOSE WINDOW ] Peripheral smear from a patient with chronic lymp... Peripheral smear from a patient with chronic lymphocytic leukemia, large lymphocytic variety. Smudge cells are also observed; smudge cells are the artifacts produced by the lymphocytes damaged during the slide preparation. Large atypical cells, cleaved cells, and prolymphocytes are also often seen on the peripheral smear and may account for up to 55% of peripheral lymphocytes. If this percentage is exceeded, prolymphocytic leukemia (B-cell PLL) is a more likely diagnosis. Peripheral blood flow cytometry is the most valuable test to confirm a diagnosis of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). It confirms the presence of circulating clonal B-lymphocytes expressing CD5, CD19, CD20(dim), CD 23, and an absence of FMC-7 staining. Consider obtaining serum quantitative immunoglobulin levels in patients developing repeated infections, because monthly intravenous immunoglobulin administration in patients with low levels of immunoglobulin G (IgG) (<500 mg) may be beneficial in reducing the frequency of infectious episodes. The differential diagnosis (see Differentials and Other Problems to Be Considered) of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) includes several other entities, such as hairy cell leukemia, which is moderately positive for surface membrane immunoglobulins of multiple heavy-chain classes and is typically negative for CD5 and CD21. Prolymphocytic leukemia has a typical phenotype that is positive for CD19, CD20, and surface membrane immunoglobulin; one half will be negative for CD5. Large granular lymphocytic leukemia has a natural killer (NK) cell phenotype (CD2, CD16, and CD56) or a T-cell immunotype (CD2, CD3, and CD8). The pattern of positivity for CD19, CD20, and the T-cell antigen CD5 is shared only by mantle cell lymphoma; these cells generally do not express CD23. Splenic lymphoma with villous lymphocytes is strongly positive for surface immunoglobulin, and positive for FMC-7, CD22, CD79b, and DBA-44. Follicular lymphoma is also strongly positive for surface immunoglobulin, positive for FMC-7, CD22, CD10, CD79b, and weak CD23. Imaging Studies Liver/spleen ultrasonographic studies may demonstrate splenomegaly in those with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). CT scanning of the chest, abdomen, or pelvis is generally not required for staging purposes in chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). However, be careful to not miss lesions such as obstructive uropathy or airway obstruction that are caused by lymph node compression on organs or internal structures. Other Tests Although not necessary for the diagnosis or staging of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL), additional molecular testing now exists that may help predict prognosis or clinical course.8,9,10,11 At present, these tests are not recommended for routine use, although this may change with further research. Chromosomal evaluation using FISH can identify certain chromosomal abnormalities of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) with prognostic significance. Patients with a deletion in the short arm of chromosome 17 (del(17p)) tend to have a worse prognosis, as well as resistance to therapy with alkylating agents and purine analogues. Patients with deletions in the long arm of chromosome 11 (del(11q)) also have a worse prognosis. The poor prognosis seen with del(17p) and del (11q) are independent of the patient's stage at presentation. Patients with these abnormalities may benefit from treatment with the monoclonal antibody alemtuzumab.12,13,14 IgVH status has shown potential as a prognostic marker for chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) as well. ZAP-70 and CD38 expression tend to correlate with unmutated IgVH and a better prognosis; however, these associations are not absolute. Further clinical information is necessary to determine the role that testing for these markers should play in the management of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). Procedures Bone marrow aspiration and biopsy with flow cytometry is not required in all cases of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL), but it may be necessary in selected cases to establish the diagnosis and to assess other complicating features such as anemia and thrombocytopenia. For example, bone marrow examination may be necessary to distinguish between thrombocytopenia of peripheral destruction (in the spleen) and that due to marrow infiltration. Consider a lymph node biopsy if lymph node(s) begin to enlarge rapidly in a patient with known chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) to assess the possibility of transformation to a high-grade lymphoma. When such transformation is accompanied by fever, weight loss, and pain, it is termed Richter syndrome. Staging Two staging systems are in common use for chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL), the modified Rai staging in the United States and the Binet staging in Europe. Neither is completely satisfactory, and both have often been modified. Because of its historical precedent and wide use, the Rai-Sawitsky system is described first, followed by the Binet. These chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) staging systems have been unable to provide information regarding the disease progression due to its heterogeneity. This lack may change in the future with better understanding of the genetic markers discussed above. Some studies have validated these molecular markers in stratifying patients into different risk groups. The original 5-stage Rai-Sawitsky staging system15 was revised in 1987 to a simpler 3-stage system. The revised Rai staging system divides patients into low-, intermediate-, and high-risk groups. * Low risk (formerly stage 0) – Lymphocytosis in the blood and marrow only * Intermediate risk (formerly stages I and II) – Lymphocytosis with enlarged nodes in any site or splenomegaly or hepatomegaly * High risk (formerly stages III and IV) – Lymphocytosis with disease-related anemia (hemoglobin <11 g/dL) or thrombocytopenia (platelets <100 x 109/L) The Binet staging system uses 3 stages — A, B, and C — based on the areas of involvement and anemia/thrombocytopenia. Areas of involvement are: head and neck lymph nodes (multiple sites counts as 1 area), axillary lymph nodes (bilateral counts as 1 area), inguinal lymph nodes (bilateral counts as 1 area), splenomegaly, and hepatomegaly. * Stage A – Hemoglobin greater than or equal to 10 g/dL, platelets greater than or equal to 100 X 109/L, and fewer than 3 lymph node areas involved. * Stage B – Hemoglobin and platelet levels as in stage A and 3 or more lymph node areas involved. * Stage C – Hemoglobin less than 10 g/dL or platelets less than 100 X 109/L, or both.Treatment Medical Care At the time of diagnosis, most patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) do not need to be treated with chemotherapy until the patient is symptomatic, or there is evidence of rapid progression of disease characterized by: * Weight loss of more than 10% over 6 months * Extreme fatigue * Fever related to leukemia for longer than 2 weeks * Night sweats for longer than 1 month * Progressive marrow failure (anemia or thrombocytopenia) * Autoimmune anemia or thrombocytopenia not responding to glucocorticoids * Progressive or symptomatic splenomegaly * Massive or symptomatic lymphadenopathy * Progressive lymphocytosis, as defined by an increase of greater than 50% in 2 months or a doubling time of less than 6 months. Patients with low risk or Binet A disease whose chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is stable require only periodic follow-up. In multiple studies and meta-analysis, early initiation of chemotherapy has failed to show benefit, and it may increase mortality in patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).16,17 As such, early therapy should only be considered in the setting of a clinical trial. The many molecular markers identified earlier have now made it possible to identify patients that are more likely to have more rapid progression of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). Studies are under way to help determine what and when the best management of these patients will be. Relatively recent data show that patients with high risk factors are more likely to progress after chemotherapy.18 Other studies are in progress to determine if high-risk patients should be treated before becoming symptomatic. For this reason patients who are identified even at an early stage should be referred for consideration in clinical trials if possible. Nucleoside analogues (ie, fludarabine, cladribine, and pentostatin) include a new group of drugs with major activity against indolent lymphoid malignancies, including chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).1 Studies have shown fludarabine to be superior to chlorambucil in chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) with higher clinical response rates, superior time to treatment failure, and better tolerance in patients over age 65 years. Fludarabine is the most extensively studied of these nucleoside analogues and is currently the most commonly used first-line therapy in chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). Responses to treatment with chlorambucil and prednisone are observed in 38-47% of patients. Patients treated with fludarabine have much higher rates (80%) of overall responses and a 37% complete remission rate. Studies using purine analogues, especially fludarabine, relative to alkylator-based therapies have shown that the response rates are superior and the progression-free interval is longer, but evidence to show prolonged overall survival is premature. The combination of fludarabine and cyclophosphamide (FC) has shown higher response rates, but direct comparative trials of fludarabine and cyclophosphamide to fludarabine alone are lacking. The combination of fludarabine and chlorambucil has been shown to result in more infections than either single agent alone. Various combination regimens have shown improved response rates in several randomized trials but also have failed to show any survival advantage. Common combination regimens include fludarabine, cyclophosphamide, and rituximab (FCR)19 ; pentostatin, cyclophosphamide, and rituximab (PCR); fludarabine, cyclophosphamide, mitoxantrone (FCM); cyclophosphamide, vincristine, and prednisone (CVP); and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). By comparing the activity of different purine nucleoside analogues (cladribine and fludarabine) combined with cyclophosphamide in previously untreated progressive CLL, Robak et al showed cladribine or fludarabine in combination with cyclophosphamide to be equally effective.20 The authors concluded that cladribine or fludarabine are safe first-line regimens for progressive CLL; however, both combinations have unsatisfactory activity in patients with 17p13 (TP53 gene) deletion. Therapy with monoclonal antibodies has been evaluated in patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). Alemtuzumab is a monoclonal antibody directed at CD52 that is approved for use in chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) as both a first-line agent and for salvage in patients with fludarabine-refractory disease. Alemtuzumab has also been shown to be effective in treating chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) with p53 mutations (del(17p13.1)). This is in contrast to rituximab, which is not effective in p53 mutation–bearing chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). Although very effective in clearing the bone marrow of disease, alemtuzumab has shown only limited activity in clearing bulky lymphadenopathy. Alemtuzumab appears to have a role in consolidation therapy for the elimination of minimal residual disease (MRD).13,14,21,22 In one study, 38% of patients treated with alemtuzumab consolidation after induction chemotherapy had molecular disease remission. Of note, 3 patients in this study developed Epstein-Barr virus–positive large B-cell lymphoma, 2 of which resolved spontaneously, and the third responded to cidofovir and immunoglobulin. The German CLL Study Group prematurely closed a phase III trial involving alemtuzumab consolidation due to severe infections in the alemtuzumab arm; however, this has not been seen in other studies to date. Other studies looking at consolidation therapy with alemtuzumab after chemotherapy have shown rates of MRD negativity from 83% to 38%, using varying induction and consolidation regimens. At present, alemtuzumab consolidation should be performed only in the setting of a clinical trial. Antiviral prophylaxis and prophylactic antibiotics for Pneumocystis carinii are recommended for use in patients receiving alemtuzumab during and for 2-4 months after treatment, or until their CD4 count is >250x109 cells. Cytomegalovirus (CMV) polymerase chain reaction (PCR) is also recommended to monitor for CMV reactivation. If CMV is detected, alemtuzumab should be discontinued, and appropriate treatment initiated until CMV becomes undetectable.

Other monoclonal antibodies in development that are undergoing study in chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) include rituximab, hLL1, epratuzumab, and lumiliximab. Rituximab as a single agent has only shown partial responses of short duration; thus, its main role is in combination chemotherapy.

Ofatumumab (Arzerra) is a new anti-CD20 monoclonal antibody. This molecule is completely humanized and is against a different epitope on the CD20. It has been approved by FDA for the treatment of patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab. In a phase II trial, the response rate was 42% (99% confidence interval [CI], 26–60), with a median duration of response of 6.5 months (95% CI, 5.8–8.3) in the heavily pretreated population. Additional studies in combination trials are being done.23

Relatively recent trials have investigated the combination of monoclonal antibodies with chemotherapeutic agents.

Rituximab has been used extensively in combination with chemotherapy. Fludarabine has been shown to downregulate CD55 and CD59, proteins involved in complement resistance, whose loss enhances the action of rituximab. Fludarabine combined with rituximab has been shown to have higher clinical remission rates than fludarabine alone in clinical trials.

Fludarabine and cyclophosphamide and rituximab (FCR) has shown clinical response rates of 76% in trials, better than either fludarabine or FC in salvage therapy for patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) that have been previously treated.

Robak et al found that rituximab in combination with fludarabine and cyclophosphamide significantly improved the outcome of patients with previously treated chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).24 Six cycles of rituximab plus fludarabine and cyclophosphamide (FCR) (n = 276) were compared with 6 cycles of fludarabine and cyclophosphamide alone (FC) (n = 276). After a median follow-up time of 25 months, rituximab significantly improved progression-free survival in patients with previously treated CLL (hazard ratio [HR] = 0.65; P <0.001; median, 30.6 mo for FCr vs 20.6 mo for FC).24 In addition, significant improvement was seen in event-free survival, response rate, complete response rate, duration of response, and time to new CLL treatment or death. Another study found that the addition of rituximab to a standard chemotherapy regimen that includes a nucleoside analogue plus an alkylating agent improved efficacy with little increase in toxicity.25 Cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR) is currently under study in clinical trials. Alemtuzumab is undergoing study in combination with fludarabine, rituximab, and the FCR regimen. A phase III study is under way in Europe that compares fludarabine with and without alemtuzumab. Alemtuzumab with rituximab appears to be well tolerated and have a high response rate; however, a short time to progression indicates that perhaps the dosing schedule needs further refinement. Phase II studies are under way investigating alemtuzumab in combination with the FCR regimen. Lenalidomide is an immunomodulatory drug (IMiD) currently approved for use in multiple myeloma and myelodysplastic syndrome with deletion of chromosome 5q. Studies have utilized this medication in treatment of patients with relapsed and refractory chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).26 Response rates of 47-38% with complete response rates of 9% and elimination of MRD have also been reported. Bone marrow transplantation has been investigated in the therapy of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). Allogenic stem cell transplantation is the only known curative therapy. The optimal timing of transplantation is still being investigated27 ; however, it is know that delay of transplantation until development of refractory disease results in worse outcomes. The effectiveness of nonmyeloablative transplantation has shown that there is a graft versus leukemia effect in chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). Autologous transplantation after high-dose conditioning has not been shown to provide a survival advantage and is not recommended outside the setting of a clinical trial. Alemtuzumab is being investigated for use in hematopoietic stem cell transplantation (HSCT). This agent may play an important role in the elimination of MRD in patients undergoing autologous transplantation, while, at the same time, the lack of CD52 on hematopoietic stem cells prevents interference with stem cell collection. The addition of alemtuzumab to nonmyeloablative conditioning regimens for allogenic HSCT appears to decrease the incidence of graft versus host disease (GVHD), but it may be associated with increased rates of CMV reactivation. Patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) demonstrate autoimmune anemia and or thrombocytopenia up to 25% of the time, and, at the same time, immune incompetence is present, characterized by a progressive profound hypogammaglobulinemia. This hypogammaglobulinemia eventually develops in almost all patients, predisposing them to a number of infections, the most common being bacterial pneumonias. Patients showing frequent bacterial infections associated with hypogammaglobulinemia are likely to benefit from monthly infusions of intravenous immunoglobulins. In a randomized, double-blind study, intravenous immunoglobulin, 400 mg/kg, or placebo was administered every 3 weeks for 1 year in 84 patients. The study showed significant reductions in the bacterial infections in the group treated with immunoglobulins, but no statistically significant difference was observed in the number of life-threatening infections requiring parenteral antibiotics. Prednisone alone, usually in a dose of 20-60 mg daily initially, with subsequent gradual dose reduction, may be useful in patients with autoimmune manifestations of the disease. Rituximab alone or in combination regimen can be very effective in eliminating the B-cell clone inducing autoimmune disorders, particularly for patients with autoimmune thrombocytopenia. The autoimmunity in B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is observed much more commonly in patients treated with fludarabine, which is known to suppress the circulating CD4+ T cells. Extremely high white blood cell counts (>300,000/µL) may produce a hyperviscosity syndrome with altered central nervous system function and/or respiratory insufficiency. Leukocytapheresis and urgent therapy with prednisone and chemotherapy may be required. Virtually all patients requiring therapy should also be given allopurinol to prevent uric acid nephropathy.
Surgical Care

* Refractory splenomegaly and pancytopenia is a common problem in patients with advanced chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) that occasionally necessitates splenectomy.
* Substantial improvements in hemoglobin and platelet counts are observed in up to 90% of patients undergoing splenectomy.
* All patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) who are to undergo splenectomy should be immunized at least 1 week in advance with Pneumovax and Haemophilus and Neisseria meningitidis vaccines.

Medication

Chlorambucil (alkylating agent) and fludarabine (antimetabolite) are commonly used in the treatment of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). Purine analogues and, in particular, fludarabine are very active against chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).

Fludarabine produces remissions in a significant proportion of patients. It appears to induce apoptosis in malignant lymphocytes upon exposure. Fludarabine in combination with cyclophosphamide (FC) has shown improved response rates over fludarabine alone, and combinations with rituximab and alemtuzumab may prove even more effective. Trials are ongoing. The role of alemtuzumab in the eradication of MRD is also under investigation.
Antineoplastic Agents

Antineoplastic agents act by inhibiting the key factors responsible for neoplastic transformation of cells.

Pentostatin (Nipent)

Inhibits adenosine deaminase, resulting in deoxyadenosine and deoxyadenosine 5+-triphosphate accumulation that may inhibit DNA or RNA synthesis causing cell death.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

4 mg/m2 IV q other wk
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Vidarabine, allopurinol, and fludarabine may increase the toxicity of pentostatin.

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; severely suppressed bone marrow (<3,000 white blood cells/m3)

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Caution in the presence of hepatic or renal insufficiency.

Chlorambucil (Leukeran)

Nitrogen mustard derivative with bifunctional alkylating activity, forms intrastrand crosslinks, interfering with DNA replication and RNA transcription and translation.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

0.1-0.2 mg/kg/d PO or 3-6 mg/m2/d PO for 3-6 wk; adjust the dose based on blood counts
Pediatric

0.4 mg/kg/dose PO q2wk initially; increase dose by 0.1 mg/kg q2wk until response occurs and/or myelosuppression occurs

Alternatively, 0.4 mg/kg/dose PO; increase dose by 0.2 mg/kg q4wk until response occurs and/or myelosuppression occurs

* Dosing
* Interactions
* Contraindications
* Precautions

None reported

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; demonstrated resistance; bone marrow suppression; breastfeeding; infection; neutropenia; thrombocytopenia

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Reduce the dose if started <4 wk after a full course of radiation therapy or another chemotherapy because of potential damage to the bone marrow.

Slow progressive leukopenia that is reversible when therapy is terminated.

Dose-dependent neutropenia appears after 3 wk of therapy and continues 10 d after termination of therapy; there's a risk of irreversible bone marrow damage if therapy is continued when neutropenia occurs.

Fludarabine (Fludara)

Nucleotide analogue of vidarabine converted to 2-fluoro-ara-A that enters the cell and is phosphorylated to form active metabolite 2-fluoro-ara-ATP, which inhibits DNA synthesis.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

25 mg/m2/d IV over 30 min qd for 5 d; repeat 5-d course q28d

Adjust the dose based on hematologic or nonhematologic toxicity.
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Combination of fludarabine with other purine analogues (eg, pentostatin) is contraindicated, because the risk of pulmonary toxicity occurring when they are used together is unacceptably high.

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; breastfeeding; bone marrow suppression

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Perform frequent peripheral blood counts to detect the development of anemia, thrombocytopenia, and neutropenia; monitor for tumor lysis syndrome.

Adjust the dose for renal impairment, severe bone marrow suppression, severe neurologic effects, or life-threatening and fatal autoimmune hemolytic anemia.

Treatment with nucleotide analogues may make stem cell collection difficult if transplantation is considered for future therapy.

Alemtuzumab (Campath)

Humanized monoclonal antibody against CD52, an antigen found on B-cells, T-cells, and almost all CLL cells. Binds to the CD52 receptor of the lymphocytes, which slows the proliferation of leukocytes.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

3-10 mg IV over 2 h initially; titrate slowly to 30 mg and administer 3 times/wk for up to 12 wk if no adverse effects.

SC administration is tolerated better than IV administration with equal efficacy.
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

May increase the virulence of live viral vaccine

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; active systemic infections; underlying immunodeficiency (eg, AIDS)

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Serious infusion reactions are the most commonly reported adverse events, as well as rigors, fever, nausea, vomiting, rash, dyspnea, and hypotension; the intensity and frequency tends to decrease with repeated exposure; premedication with acetaminophen, diphenhydramine, hydrocortisone, and dose titration have been shown to reduce infusion reactions; infusional events are significantly reduced when the drug is given SC rather than IV (local skin reactions [edema/erythema] may occur with SC administration); the majority of patients will have transient cytopenias, particularly in patients with preexisting cytopenias; autoimmune hemolytic anemia has been reported; infectious complications include fatal bacterial, viral, fungal, and protozoan infections; CMV reactivation is the most commonly reported opportunistic infection; prophylaxis with valganciclovir has been shown to be effective; antiviral prophylaxis is effective in preventing HSV and VZV reactivation and is recommended in all patients; PCP prophylaxis is also recommended; posttransplant lymphoproliferative disorders have been reported; possible cardiotoxicity in the form of arrhythmia and CHF has been reported; there is a potential impact on spermatozoa in vitro, but no in vivo reproductive complications have been reported (may be due to advanced age of patients; drug does not appear to achieve significant concentrations in seminal fluid).

Rituximab (Rituxan)

Humanized murine monoclonal antibody against CD20, antigen found on B-cells; CLL cells are typically CD20(dim). Due to low levels of CD20 expression, increased doses of rituximab may be necessary. Binds CD20 on lymphocytes and induces apoptosis as well as initiating complement-mediated killing of bound cells.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Used in clinical trials alone or in combination with fludarabine, with or without cyclophosphamide
375 mg/m2 IV q 28 d as part of FCR combination therapy
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

May increase the virulence of live viral vaccine; increased risk of infection with natalizumab; increased nephrotoxicity in combination with cisplatin

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; active systemic infections

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Anaphylactic/anaphylactoid reactions can occur; hypotension, bronchospasm, angioedema, pulmonary infiltrates, and ARDS may occur; MI or life-threatening cardiac arrhythmias can occur; fatal infusion-related reactions have occurred within up to 24 h of dose administration; Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported; reactivation of hepatitis B has been reported; neutropenia, anemia, thrombocytopenia may occur.

Ofatumumab (Arzerra)

Anti-CD20 human monoclonal antibody that inhibits B-cell activation in early stages. Indicated for chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab. Effectiveness based on objective responses. Improvement in disease or symptoms, or increased survival was not demonstrated.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

First dose: 300 mg IV for 1 dose
Doses 2-8 (initiate 1 wk after first dose): 2000 mg IV qwk for 7 doses
Doses 9-12 (initiate 4 wk after eighth dose): 2000 mg IV q4wk for 4 doses
Regimen totals 12 doses
Pediatric

Not establishedFollow-up
Further Inpatient Care

Chemotherapy for (chronic lymphoid leukemia, CLL) is typically given in an outpatient setting.

Some patients with (chronic lymphoid leukemia, CLL) require admission if they develop febrile neutropenia. This is treated in the usual fashion by giving broad-spectrum intravenous antibiotics after obtaining blood cultures. The antibiotics commonly used on empiric grounds are ceftazidime, cefepime, or imipenem. Aztreonam can be used in penicillin-allergic patients. If patients have indwelling central venous access devices and appear septic, consider adding vancomycin.
Further Outpatient Care

Following chemotherapy, patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) are prescribed antiemetics such as Compazine for use, as needed. Patients are advised to inform their hematologist/oncologist if they develop fever.

Growth factors may be used in order to decrease the length of neutropenia following chemotherapy in patients with (chronic lymphoid leukemia, CLL).
Complications

The hypogammaglobinemia and impaired T-cell function associated with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) predispose patients to potentially serious infections. Patients who demonstrate a pattern of repeated infections, such as pneumonia and septicemia, should be treated monthly with prophylactic parenteral gamma globulin.

Anemia secondary to bone marrow involvement with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL), splenic sequestration of red blood cells, and autoimmune hemolytic anemia associated with a positive Coombs test are included in the differential diagnosis of a patient with anemia who has chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) (see Differentials and Other Problems to Be Considered).

Thrombocytopenia: The causes of low platelets in patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) are very similar to the causes of anemia in patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) and include bone marrow involvement, splenic sequestration, and immune thrombocytopenia.

Richter syndrome or Richter transformation refers to the transformation of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) into an aggressive large B-cell lymphoma and is seen in ~3-10% of cases. Patients will often present with symptoms of weight loss, fevers, night sweats, muscle wasting, and increasing hepatosplenomegaly and lymphadenopathy. Lymph node biopsy is necessary for the diagnosis. Epstein-Barr virus (EBV) may play a role in transformation. Immunosuppression has also been implicated.
Prognosis

The prognosis of those with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) varies widely at diagnosis, depending on the stage at diagnosis as well as the presence or absence of high risk markers at time of diagnosis. Median survival once treatment is initiated is ~4.5 years; however, this number is in constant flux, as new therapeutic regimens are being developed for chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).
Miscellaneous
Medicolegal Pitfalls

Mantle cell lymphoma can have a clinical presentation very similar to chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL), but the prognosis is much poorer. The duration of response to treatment can be shorter, and the clinical course of mantle cell lymphoma tends to be more aggressive. Mantle cell lymphoma can be distinguished from chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) expressing CD5 and CD19 but not CD23 antigen, which is expressed in chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). Mantle cell lymphoma typically expresses FMC-7. Importantly, mantle cell lymphoma expression of CD20 is bright, whereas it is dim in chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL).

Special Concerns

Patients with CLL are prone to usual and unusual infections. Pneumococcal and flu vaccines are recommended.