Chapter 55: Chronic Lymphocytic Leukemia and Related Diseases

• Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells characterized by blood and marrow lymphocytosis. Varying degrees of lymphadenopathy, splenomegaly, and blood cytopenias develop as the neoplasm progresses.

• CLL is the most prevalent adult leukemia in Western societies.

• The prevalence of CLL in the United States in 2014 was 126,553 patients. There are approximately 15,700 new cases annually.

• CLL is uncommon before age 40 years and is extremely rare in children or young adults.

• The incidence of the disease increases logarithmically after age 45 years.

• Median age at diagnosis is approximately 70 years.

• CLL is uncommon in Asian countries and in Asians immigrants to the Americas or Europe.

Environmental Factors

• Radiation or chemotherapy has not been shown to be a risk factor for developing CLL.

• Exposure to occupational chemicals, such as solvents, paints, or pesticides, has not been established to be a risk factor for CLL.

• There is a higher frequency of living or working on a farm in patients with CLL compared to those without the disease.

Hereditary Factors

• Familial occurrence is most evident in CLL compared with other leukemias.

  — Multiple cases of CLL are found within a single family with greater frequency.

  — Up to 10% of patients with CLL have a first- or second-degree relative with CLL.

  — First-degree relatives of patients with lymphoplasmacytic lymphoma or Waldenström macroglobulinemia (Chap. 69) have a greater than threefold increased risk of developing CLL.

• Genetic factors contribute to increased incidence of CLL.

  — Polymorphisms in the gene encoding CD5 (located at chromosome 11q13), CD38 (located at chromosome 4p15), or tumor necrosis factor-α, and other genes mapping to chromosome 13q21.33-q22.2.

Disease Biology

• CLL cells typically express CD5, CD19, CD23, and low levels of CD20.

• CLL cells have surface immunoglobulins reactive with self-antigens.

• CLL cells have defective apoptosis supported by the microenvironment.

• CLL cells overexpress BCL-2.

• CLL is characterized by dysregulation in both cellular and humoral immunity.

• CLL cells depend on constitutive activation of the B-cell receptor pathway for survival; the survival signals are transduced through LYN, PI3K, SYK, and BTK pathways.

Monoclonal B-Cell Lymphocytosis

• CLL has an initial phase referred to as monoclonal B-cell lymphocytosis. In most cases, this is not apparent at diagnosis because it is asymptomatic and is detected by flow cell analysis of blood lymphocytes.

• Patients have no lymphadenopathy; no splenomegaly; otherwise normal blood counts; and no fever, night sweats, or unexplained weight loss.

• The incidence of monoclonal B-cell lymphocytosis increases dramatically after 40 years of age.

• Approximately 15% of healthy individuals, who have first-degree relatives with two or more family members with CLL, have blood monoclonal B cells of the CLL B-cell immunophenotype.

• The immunophenotype of the monoclonal B cells may be (1) similar to CLL in approximately 80% of cases (CD5CD23-positive, CD20-dim); (2) atypical CLL (CD5CD23-positive, CD20-bright); or (3) non-CLL type (CD5CD23 negative).

• Monoclonal B-cell lymphocytosis is diagnosed when the number of these cell is less than or equal to 5000 × 10⁹/L. CLL is diagnosed with monoclonal B-cell counts of more than 5000 × 10⁹/L cells.

• Monoclonal B-cell lymphocytosis evolves to CLL at a rate of approximately 1% per year.

• Most patients are asymptomatic at diagnosis. The disease is detected because of a routine blood test showing lymphocytosis or a physical examination confirming lymph node enlargement.

• Some patients have fatigue, reduced exercise tolerance, or malaise.

• Some cases may present with recurrent, usually upper respiratory, infections.

• Patients with advanced disease may have weight loss, recurrent infections, night sweats, fever, and/or symptomatic anemia.

• An unusual finding is insect (mosquito) bite sensitivity with exaggerated cutaneous inflammatory reactions.

• Lymph nodes are generally not fixed or tender.

• The nodes may increase with infections and return to the previous size after resolution.

• Mild to moderate splenomegaly is seen commonly and can cause mild thrombocytopenia.

• Extranodal involvement can include:

  — Hepatomegaly

  — CLL cell infiltrates in the scalp, subconjunctivae, prostate, gonads, or pharynx

  — Pulmonary infiltrates that can be detected on chest imaging

  — Gastrointestinal ulceration, gastrointestinal bleeding, or malabsorption

  — Leukemic cell infiltration of the central nervous system that although unusual, may produce headache, meningitis, cranial nerve palsy, obtundation, or coma

Blood Findings

• CLL is diagnosed with a monoclonal B-cell count of greater than 5000 × 10⁹/L.

• The blood film has an increase in small, normal appearing lymphocytes to a degree related to lymphocyte count; see Figure 55–1.

  — Approximately one in five to ten CLL lymphocytes in the blood are ruptured during blood film preparation and are referred to as smudge cells.

• Fifteen percent of patients present with normocytic anemia.

• Twenty percent have a positive red cell direct antiglobulin test at some time in the disease.

• Thrombocytopenia caused by antiplatelet antibodies may develop at any time. In advanced disease, thrombocytopenia also may be a result of marrow replacement and/or splenic sequestration.

• Serum lactic dehydrogenase (LDH) and beta-2 microglobulin. Elevation predicts the likelihood of a more aggressive disease.

Marrow Findings

• Marrow is invariably infiltrated with small lymphocytes in one of four patterns:

  — Interstitial (or lacy): 30%; associated with a better prognosis

  — Nodular: 10%

  — Mixed interstitial/nodular: 25%

  — Diffuse marrow replacement: 25%; associated with a poorer prognosis

Lymph Node Findings

• Lymph nodes are affected by diffuse infiltrate of small lymphocytes that efface the node architecture and invade the subcapsular sinus.

• Note that this finding is not required for diagnosis.

CLL Cell Immunophenotype

• Diagnosis of CLL requires sustained monoclonal lymphocytosis of greater than 5000 × 10⁹/L cells.

• The diagnosis of CLL requires establishing the monoclonal nature of the lymphocytosis by flow cytometry according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria. For example, one usually determines if the light chain expression is either λ or κ (monoclonal) and not both (polyclonal).

• CLL cells typically express CD5CD19,CD23+CD20dim) and CD10CD103–, with low expression of surface immunoglobulin and low-level or absent expression of CD22 and CD79b.

• FMC7, a monoclonal antibody that binds an epitope of CD20 formed when this surface antigen is present at high density, typically does not react with CLL cells.

• CD38 can be detected on the surface of CLL cells using flow cytometry. A level of expression greater than 30% predicts the likelihood of a more aggressive course.

• CD49d expression in more than 30% of the CLL cells predicts the likelihood of a more aggressive course.

Serum Protein and Immunoelectrophoresis

• Most common finding is hypogammaglobulinemia.

• Reduction in the serum levels of IgM precedes that of IgG and IgA.

• Five percent of patients have a serum monoclonal immunoglobulin.

• In some cases, there is defective and/or unbalanced immunoglobulin chain synthesis by the leukemic B-cell clone, resulting in μ heavy-chain disease (see Chap. 70) and/or immunoglobulin light-chain proteinuria.

Cytogenetic Studies

Chromosome 13 Anomalies

• The most common genetic abnormality found in about half of all patients is deletion of part of the long arm of chromosome 13, specifically at 13q14.-23.1 telomeric to the retinoblastoma gene (RB-1) and centromeric to and including the D12S25 region.

• Loss of microRNA miR15 and/or miR16–1 might contribute to leukemogenesis and account for the frequent deletions that are observed at 13q14.3.

Chromosome 12 Anomalies

• Trisomy 12 is the second most common abnormality, found in about 20% of patients; half of these have trisomy 12 only.

• This abnormality may not be a primary factor in leukemogenesis but is probably acquired during disease evolution.

Chromosome 11 Anomalies

• Approximately 20% of patients have a deletion(s) in the long arm of chromosome 11, termed 11q-, which is associated with more aggressive disease.

• Associated with younger age at diagnosis (< 55 years) and tend to have bulky cervical lymphadenopathy than patients without such genetic changes.

Chromosome 17 Anomalies

• Deletions in the short arm of chromosome 17 at 17p13.1 are in less than 10% of all patients. The critical gene in the region that typically is deleted is TP53.

• Patients with 17p– and/or TP53 mutations generally have more advanced disease, a higher leukemia-cell proliferative rate, a shorter survival, and greater resistance to first-line therapy.

• These patients are more likely to transform to an aggressive B-cell lymphoma (referred to as a Richter transformation).

Other Chromosome Abnormalities

• Abnormalities involving chromosomes 6, 14, and 18 are less common.

Fluorescence in situ Hybridization

• Using fluorescence in situ hybridization (FISH), the leukemic cells from almost all CLL patients have clonal chromosomal abnormalities.

Immunoglobulin Heavy Chain Gene Mutations

• Two groups of CLL patients are distinguished by the extent that their immunoglobulin heavy chain variable region genes (IGHV) have undergone somatic mutation.

  — Approximately 40% of CLL patients have leukemia cells that express nonmutated IGHV genes and have a greater tendency for disease progression.

  — Approximately 60% express IGHV mutated genes with levels of base substitutions that distinguish them from their germ-line counterparts. Patients with mutated IGHV have a significantly longer treatment-free interval, longer remission duration if therapy is required, and longer survival after diagnosis.

• One noted exception to this distinction is represented by patients who have leukemia cells that use a particular immunoglobulin gene, designated IGHV3–21.

  — Patients who have CLL cells that use a mutated IGHV3–21 gene together with a λ immunoglobulin light chain encoded IGHV3–21 have a risk of aggressive disease similar to that of patients who have leukemia cells that express unmutated IgHv genes.

• The diagnosis is by detection of a monoclonal B-cell lymphocytosis of at least 5000 cells × 10⁹/L.

• A lymphocyte doubling time of less than 12 months has been shown to be associated with a more aggressive course.

• Flow cytometry of blood cells should show the cells to be monoclonal CD5CD19CD23-positive, CD20-dim, express dim surface immunoglobulin, and be CD10CD79b-negative.

• Neither a marrow aspirate and biopsy nor lymph node biopsy is required for the diagnosis in the overwhelming majority of patients.

• Computed tomography (CT) or other imaging is not necessary for the initial evaluation of patients with CLL. Positron emission tomography (PET) can be useful if a Richter transformation is suspected.

• FISH cytogenetic studies should be done to identify the abnormalities commonly seen in patients with CLL (Table 55–1).

• Patients with anemia without reticulocytosis should be evaluated for their anemia including serum vitamin B₁₂, red cell folic acid levels, serum ferritin, and tests for gastrointestinal bleeding, as appropriate.

• Patients with CLL frequently have hypogammaglobulinemia and occasionally have a monoclonal Ig; serum electrophoresis and measures of serum IgG, IgM, and IgA are important.

• The assessment of IgHv somatic mutation by a polymerase chain reaction (PCR) assay is an important prognostic tool. Patients with less than 2% homology in their nucleotide sequence compared to consensus germline sequence are considered unmutated (ie, about 40% of patients) and have a poorer prognosis.

• Table 55–2 summarizes frequently used prognostic indicators.

Determining the Clinical Stage of CLL

• One of two staging systems is usually used: the Rai system defined in Table 55–3 or the Binet system characterized in Table 55–4.

• Both these systems consider the degree and distribution of lymphadenopathy and the presence of anemia and or thrombocytopenia, but the Rai staging classification considers hepatic and splenic enlargement, whereas the Binet staging system does not.

• See Table 55–5 for the immunophenotype of chronic B-cell leukemias/lymphomas.

• Monoclonal lymphocytosis versus causes of polyclonal lymphocytosis (see Chap. 49)

• Prolymphocytic leukemia (see discussion later in this chapter)

  — More than 50% of circulating leukemic lymphocytes have prolymphocytic morphology, with a larger size than CLL cells and a prominent nucleolus.

  — There are high levels of CD79b and surface immunoglobulin and low levels of CD5.

• Hairy cell leukemia (see Chap. 56)

• Lymphomas with circulating neoplastic cells (see Chap. 60)

• Small cell lymphocytic lymphoma

  — Low-grade small lymphocytic B-cell lymphoma is closely related to B-cell CLL in its biology and clinical features.

  — There is lymph node involvement.

  — There is no overt blood or marrow involvement.

• Mantle cell lymphoma (see Chap. 62)

  — It expresses many of the same surface antigens as CLL B cells.

  — It does not express CD23.

  — The t(11;14) is characteristic of mantle cell lymphoma.

• Splenic marginal zone lymphoma (SMZL) (see Chap. 63)

  — This is commonly called splenic lymphoma with villous lymphocytes.

  — SMZL has a mature B-cell phenotype and expresses IgM and IgD but typically lacks expression of CD23, CD43, CD10, BCL-6, and cyclin D.

  — Neoplastic B cells have weak or absent expression of CD5

• Lymphomas of follicular center cell origin (see Chap. 61)

  — Small cleaved cell lymphomas express the CD10 (CALLA) antigen.

• Lymphoplasmacytic leukemias

  — These express CD38, PCA-1, CD56, and CD85, but there is low-level or lack of expression of CD19, CD20, CD24, CD72, and HLA-DR.

• Waldenström macroglobulinemia (see Chap. 69)

• Myeloma (see Chap. 68)

• T-cell lymphoproliferative disorders (see Chap. 66)

• T-cell CLL and T-cell prolymphocytic leukemia (see discussion later in this chapter)

• Large granular lymphocytic leukemia (see Chap. 57)

• Adult T-cell leukemia/lymphoma (see Chap. 66)

• Cutaneous T-cell lymphomas (see Chap. 65)

General Considerations

• Not all patients require treatment at time of diagnosis.

• No evidence of a survival advantage apparently occurs if therapy is initiated when the patient is asymptomatic.

• Presence of del(17p) predicts resistance to standard chemotherapy and thus an inferior prognosis.

• Presence of del(11q) has significantly lower response rates to single-agent chemotherapy; outcomes are improved with fludarabine-based combination therapy.

Indications for Treatment

• Treatment is indicated for patients with active disease, including those with:

  — Constitutional symptoms, such as weakness, painful lymphadenopathy, fever, night sweats, and weight loss

  — An increase of 50% or more in blood lymphocyte count over a 2-month period or lymphocyte count doubling time of less than 6 months

  — Rapidly enlarging lymph nodes, spleen, or liver.

  — Autoimmune complications (eg, autoimmune hemolytic anemia or autoimmune thrombocytopenia). Poor response to therapy (typically glucocorticoids) directed at the autoimmunity is an indication for treatment of the underlying CLL.

  — Repeated episodes of infection. Patients with hypogammaglobulinemia with infection should receive periodic infusions of gamma globulin.

  — Transformation of CLL cells to a more aggressive histology causing worsening anemia and/or thrombocytopenia (prolymphocytic or Richter transformation)

Approach to Therapy

Localized Disease

• Irradiation remains a useful technique for localized treatment.

• Delivery of 200 Gy often can result in rapid shrinkage of lymph nodes or masses.

Initial Treatment of Active Disease

• Goals of therapy are to ameliorate symptoms and improve survival.

• No therapy, other than possibly allogeneic hematopoietic stem cell transplantation, has been shown to cure CLL.

• Several initial treatment options exist; most have not been directly compared. Enrollment in a clinical trial is recommended.

• Initial therapy choice should be based on goals of treatment as well as patient (age, comorbidities) and high-risk disease characteristics such as del(17p) or del(11p).

• Regimens differ in rates of complete remission, time to progression, and toxicities.

  — Single agent chemotherapy with drugs such chlorambucil, cyclophosphamide, bendamustine, and fludarabine can be utilized.

  — Combination chemotherapy produces a higher response rate and higher complete remission rate but at the risk of more toxicity.

Fludarabine-based therapy

• Combination therapy with fludarabine and rituximab (FR) is often used. (Table 55–6)

• There is a higher response rate and higher complete remission rate but more toxicity with a combination of fludarabine, cyclophosphamide, and rituximab (FCR). This regimen is often considered a standard of care for physically fit patients but should be used cautiously in older patients.

• Prognosis of patients with del(11q) is improved with FCR therapy; however, that of del(17p) remains poor.

Bendamustine-based Therapy

• Bendamustine with rituximab (BR) has been tested in both patients with untreated CLL and relapsed disease.

• In the phase III, multicenter, CLL10 trial of 564 patients with previously untreated CLL, good performance status and low comorbidity burden randomized to FCR or BR, the overall response rates were similar, but complete response rates were higher in the FCR arm (40% FCR, 31% BR). FCR was more toxic.

Pentostatin-based Therapy

• Combination therapy results in higher response rates than with single agent.

• Pentostatin can be used instead of fludarabine, but the relative effectiveness of the most common combination (pentostatin, cyclophosphamide, and rituximab) is not established.

Chlorambucil-based Therapy

• This agent is often used as single agent in older patients who are not candidates for combination therapy.

• Combination of chlorambucil with an anti-CD 20 monoclonal antibody (eg, rituximab, obinutuzumab, ofatumumab) results in higher response rates and longer progression-free survival but has greater toxicity.

Anti-CD20 Monoclonal Antibodies

• Rituximab, ofatumumab, and obinutuzumab are all effective in CLL.

  — Rituximab as a single-agent resulted in only partial responses in a minority of CLL patients. Rituximab has been most widely used and is more effective in combination therapy.

  — Ofatumumab is approved by the US Food and Drug Administration (FDA) for use (1) in combination with chlorambucil for the treatment of patients with previously untreated CLL who are not candidates for fludarabine-based treatment and (2) as a single agent for patients with relapsed or refractory disease.

  — Obinutuzumab is approved by the FDA for use in combination with chlorambucil for patients with previously untreated CLL. It is significantly more active than chlorambucil plus rituximab).

Ibrutinib

• This Bruton tyrosine kinase (BTK) inhibitor with a high response rate in patients with relapsed CLL and a high level of activity as initial therapy in patients with deletion 17p. It is FDA approved for these two indications.

  — Even in patients with relapsed disease, the responses are often durable as long as the patient continues to tolerate the drug.

  — The most frequent side effects are diarrhea, nausea, fatigue, and a higher incidence of atrial fibrillation.

  — Some patients will have a bleeding diathesis that makes combining ibrutinib with anticoagulants—particularly warfarin—problematic.

  — Patients starting on ibrutinib will typically develop lymphocytosis that will resolve spontaneously over time.

Therapy of Relapsed/Refractory CLL

• Patients with asymptomatic recurrent CLL may not require therapy but should be followed closely for developing of active disease, which requires therapy.

• Choice of therapy at relapse should be based on quality and duration of response to prior therapy.

  — Patients who relapse more than 1 year after an initial response may be retreated with same therapy as for initial treatment. Ibrutinib or rituximab plus idelalisib are appropriate alternatives.

  — The combination of rituximab and idelalisib, an oral inhibitor of phosphoinositide 3′-kinase (PI3K) resulted in an overall response rate of 81% versus rituximab and placebo. Idelasib plus rituximab was FDA approved in 2014 for treatment of patients with relapsed CLL with significant comorbidities.

  — Patients with early relapsed CLL or whose disease is refractory to initial therapy should be treated with a second-line regimen; young patients with good performance status and few comorbidities may be considered for hematopoietic stem cell transplantation on a clinical trial. The combination of rituximab and idelalisib, an oral inhibitor of phosphoinositide 3′-kinase (PI3K) resulted in an overall response rate of 81% versus rituximab and placebo. Idelasib plus rituximab was FDA approved in 2014 for treatment of patients with relapsed CLL with significant comorbidities.

• Palliation of symptoms may be achieved with rituximab, ofatumumab, and glucocorticoids with only moderate toxicity. Splenectomy or splenic irradiation may be useful for patients with splenomegaly and severe cytopenias refractory to systemic therapy. Localized irradiation may improve symptoms related to bulky disease or impingement on vital organs.

Hematopoietic Stem Cell Transplantation

• Due to potential morbidity and mortality associated with hematopoietic stem cell transplantation (HSCT), only select patients are considered and, if possible, HSCT should be performed in context of a clinical trial.

• Ideal timing is unknown. May be considered for patients with clinically aggressive relapsed/refractory CLL or those with high risk genetic factors, including del(17p) and del (11q).

Autologous HSCT

• Preparative regimen is well tolerated.

• Risk of recurrent disease after transplant is high.

• This type of HSCT may prolong disease-free survival.

Allogeneic HSCT

• This procedure may eradicate the leukemia cells to the levels that cannot be detected using sensitive molecular techniques to detect clonal immunoglobulin gene rearrangements.

• Patients who relapse following allogeneic HSCT may respond to infusions of donor leukocytes.

Nonmyeloablative Allogeneic HSCT

• Preparative regimen is better tolerated than standard allogeneic HSCT.

• Complete chimerism, as well as best response, is not achieved immediately after transplantation but may take over 3 months to develop.

• Patients with refractory CLL can experience eradication of minimal residual disease (MRD) several weeks following transplant, providing evidence of a graft-versus-leukemia effect.

Response Criteria

• Response criteria for patients who have had prior therapy are the same as those used for initial therapy.

Complete Response

• This requires that the patient is free of clinical disease for at least 2 months after therapy.

• Satisfactory blood counts:

  — Hemoglobin > 11 g/dL; no red cell transfusion requirement

  — Neutrophil count at least 1.5 × 10⁹/L

  — Lymphocyte count ≤ 4.0 × 10⁹/L

  — Platelets ≥ 100 × 10⁹/L

• There is an absence of fever, night sweats, weight loss, or other disease-related symptoms.

• There is an absence of hepatosplenomegaly or detectable adenopathy.

• Marrow has less than 30% lymphocytes and lacks pathologic lymphoid nodules.

• If the marrow is found to be hypocellular, a repeat marrow biopsy should be performed after 4 to 6 weeks, provided blood counts have recovered. The marrow biopsy should not exceed a period of 6 months after the last treatment.

Partial Response

• For at least 2 months after therapy, the patient must have at least:

  — A 50% reduction in the number of blood lymphocytes

  — A 50% reduction in lymphadenopathy or hepatosplenomegaly

• Absolute neutrophil count of at least 1.5 × 10⁹/L or greater than 50% improvement over that noted prior to therapy

• Blood platelets >100 × 10⁹/L

• Hemoglobin >11 g/dL

• A 50% improvement in platelet or red cell counts over pretreatment values without transfusion

• Patients who satisfy the criteria for a complete response but who have persistent lymphoid nodules in the marrow are classified as having a nodular partial response.

Progressive Disease

• New lymphadenopathy; an increase in lymphadenopathy of greater than or equal to 50%

• An increase in the liver or spleen size of greater than 50% or the appearance of hepatomegaly or splenomegaly while on therapy

• An increase in the absolute lymphocyte count of greater than or equal to 50%

• Transformation to a more aggressive histology (eg, Richter syndrome), which should be established by lymph node biopsy

Refractory Disease

• Patient who experiences disease progression within 6 months of completing therapy is considered to have disease that is refractory to such therapy.

Minimal Residual Disease

• Improved leukemia-cell detection methods using flow cytometry or PCR can reveal patients in complete response who have residual CLL cells.

• Patients who experience eradication of minimal residual disease (MRD) apparently have a longer treatment-free survival than do patients who have achieved a complete response but have persistent MRD.

Disease Complications

Infection

• Infection is a major cause of morbidity or mortality.

• Susceptibility to infection correlates with hypogammaglobulinemia and/or T-cell lymphocytopenia.

  — Advanced-stage disease, hypogammaglobulinemia, and low levels of specific antibodies to pneumococcal capsular polysaccharide are associated with severe or multiple infections.

• Monthly intravenous administration of pooled normal serum immunoglobulin (intravenous immune globulin [IVIG] at 240 to 400 mg/kg every 3 to 4 weeks) may decrease frequency of infection.

Autoimmune Complications

• These conditions include autoimmune hemolytic anemia, autoimmune thrombocytopenia, and pure red cell aplasia.

• In the majority of patients, the nonmalignant B-cell clone produces the autoantibody.

• Glucocorticoids have been the mainstay of treatment for autoimmune hemolytic anemia and autoimmune thrombocytopenia. Many patients relapse after discontinuation and may need therapy with IVIG or rituximab.

• Pure red cell aplasia is rare; treatment with glucocorticoids, cyclophosphamide, and/or cyclosporine result in slow correction of anemia over several weeks.

Second Malignancies

• Most frequent are melanoma, sarcoma, colorectal or lung cancers, or myeloma.

• Higher recurrence rates of basal cell carcinoma occur in individuals after Mohs’ surgery (a surgical procedure used to treat common types of skin cancer) than in the general population.

• The incidence of developing Merkel cell carcinoma (rare and highly aggressive cancer in which malignant cancer cells develop on or just beneath the skin and in hair follicle is greater.

• The risk of developing more aggressive and/or metastatic squamous cell skin carcinomas is greater than in the general population.

• Multiple myeloma occurs at 10 times the expected rate in patients with CLL but evidently does not arise from the same malignant B-cell clone.

• Both untreated and treated CLL patients can develop acute myelogenous leukemia or myelodysplastic syndrome.

• Therapy-related acute myelogenous leukemia may develop after treatment with single-agent deoxyadenosine analogs, such as fludarabine or cladribine.

Richter Transformation

• This condition represents transformation to an aggressive, high-grade, large B-cell lymphoma.

• It can occur at any time in the course of CLL.

• It occurs in approximately 3% of patients at a median of 2 years after diagnosis of CLL.

• It can develop in patients who had not received chemotherapy.

• It arises from the original CLL clone.

• Chromosomal abnormalities are complex and include:

  — del 8p, del 9p, del 11q (11q23), 12(+), del 13q, 14q(+), del 17p, del 20, and/or translocations involving chromosome 12

  — Trisomy 12 and chromosome 11 abnormalities (which are more frequent)

• There is a higher incidence of P53 mutations at transformation.

• Three independent risk factors for transformation are identified.

  — High-level expression of CD38 by leukemia B cells

  — Absence of leukemia-cell deletion at 13q14

  — Leukemia cell expression of certain IgHV genes, notably IGHV4-39

• Clinical and laboratory features include the following:

  — Increased serum LDH activity in approximately 80% of patients

  — Rapid lymph node enlargement in approximately 65%

  — Fever and/or weight loss in approximately 60%

  — Monoclonal gammopathy in approximately 45%

  — Extranodal disease in approximately 40%

• Not all patients with CLL that have rapid lymph node enlargement have Richter transformation.

• Infection with herpes simplex virus can cause acute lymphadenitis.

• Occasional cases of Richter transformation have histology resembling that of Hodgkin lymphoma (see Chap. 59). This is termed Richter syndrome with Hodgkin lymphoma features.

  — Richter syndrome with Hodgkin lymphoma features may respond favorably to therapy for Hodgkin lymphoma.

• Treatment similar to that of patients with high-grade lymphoma (see Chap. 60).

• Encouraging responses have been observed with OFAR regimen (oxaliplatin, fludarabine, cytarabine, rituximab).

• Median survival is 5 months after transformation.

CLL/Prolymphocyte and Prolymphocytic Transformation

• Fifteen percent of patients with CLL have a mixture of small lymphocytes and prolymphocytes (PL), the latter accounting for 10% to 50% of the lymphoid cells. These patients are considered to have CLL/PL.

• In 80% of CLL/PL cases, the proportion of PLs remains stable.

• Twenty percent of patients with CLL/PL undergo prolymphocytic transformation with greater than 55% of the leukemia cells having PL morphology (see below).

  — Progressive splenomegaly is characteristic.

  — Patients have a mean survival of 9 months after transformation.

Acute Lymphoblastic Leukemia

• Rare complication

• Can arise from same cell clone as CLL

• Associated with high levels of expression of c-MYC and surface immunoglobulin

Prognosis for CLL

• No established cures for CLL exist.

• Spontaneous remissions are rare.

• CLL varies substantially between different patients depending on clinical stage and/or presence or absence of certain disease features associated with progression and/or adverse clinical outcomes.

• Female patients have longer survival.

• Male-to-female ratio is greater in patients diagnosed at younger ages (< 65 years).

• CLL relegated deaths occur more frequently in younger patients.

• Five-year relative survival is approximately 70%, 70%, 65%, and 40% for age groups younger than 40, 40 to 59, 60 to 79, and 80+ years, respectively, indicating that the 5-year survival does not vary significantly between the different age groups under the age of 80 years.

• Risk of CLL-unrelated deaths and secondary malignancies predominate in older age groups.

Definition

• PLL is a clinical and morphologic variant of CLL.

• It is a subacute lymphoid leukemia.

• Incidence is less than 10% that of CLL.

• Diagnosis of PLL requires that at least 55% of the circulating leukemic lymphocytes have prolymphocytic morphology.

Etiology and Pathogenesis

• PLL is a de novo leukemia as are most chronic and subacute lymphocytic leukemias.

Cytogenetics

• Karyotype of the leukemia cells from many patients displays the 14q+ abnormality.

• Trisomy 12 is another recurrent abnormality.

• Deletions of the long arm of chromosome 6 (6q-) and rearrangement affecting chromosomes 1 and 12 are occasionally observed.

• The most common abnormalities are as follows:

  — 13q14 at 46%

  — Trisomy 12 at 21%

  — 14q32 at 21%

• Loss of heterozygosity at 17p13.3 associated with inactivating mutations in the TP53 gene is observed in as many as three-fourths of the cases examined.

Cytogenesis

• Mature B-cell origin that have undergone immunoglobulin gene rearrangement.

  — IGHV4-34 genes.

Clinical Features

• Fifty percent of patients are older than 70 years.

• Patients often have advanced disease at presentation.

• Presenting symptoms include fatigue, weakness, weight loss, an acquired bleeding tendency, and early satiety because of splenomegaly.

• Massive splenomegaly occurs in about two-thirds of patients.

• Patients typically have relatively little palpable lymphadenopathy.

• In rare cases, patients may present with leukemic meningitis, leukemic pleural effusion, or malignant ascites.

Therapy, Course, and Prognosis

• Indications for treatment include the following:

  — Disease-related symptoms

  — Symptomatic splenomegaly

  — Progressive marrow failure

  — Blood prolymphocyte count > 20 × 10⁹/L

  — Hemoglobin < 10 g/dL in the absence of hemolysis

  — Platelet count < 100 × 10⁹/L

• Treatment is with alkylating agents similar to those used for CLL, or combinations such as CHOP, yield response rates of 20%.

• Fludarabine or cladribine may be effective.

• Monoclonal antibodies (eg, alemtuzumab, rituximab), alone or in combination with chemotherapy, may be effective.

• Splenic irradiation with 1000 to 1600 Gy delivered to the splenic bed has been advocated as a palliative therapy for the disease.

Definition

• Because of its relative aggressive clinical behavior, what formerly had been called T-cell CLL is categorized in the REAL classification as T-cell PLL regardless of leukemia cell morphology (see Chap. 54).

• Incidence is less than 5% that of CLL.

Etiology and Pathogenesis

• Etiology is unknown.

• There is a 3:2 male-to-female predominance.

• Incidence is five to six times higher in the southern islands of Japan than in Western societies.

• Infection with human T-lymphotropic virus type I (HTLV-1) may play a pathogenic role in a subset of patients.

Genetics

• Chromosomal regions most often overrepresented are:

  — 8q at 75%, 5p at 62%, and 14q at 37%, as well as 6p and 21 both at 25%

• Chromosomal regions most often underrepresented are:

  — 8p and 11q at 75%, 13q at 37%, and 6q, 7q, 16q, 17p, and 17q at 25%

• Less common cytogenetic rearrangements are:

  — del(6)t(X;6), (p14;q25), del(13)t(13;14)(q22;q11), t(5;13)(q34;p11), r(17)(p13q21), and t(17;20)(q21;q13)

• Alterations on chromosomes 5, 6, 8, 11, 13, 14, 17, and/or 21 apparently cluster into discrete regions that may contain genes that are deleted or amplified during leukemogenesis or disease progression.

• Strong association with mutations in the ataxia-telangiectasia–mutated gene that maps to chromosome region 11q22.3–23.1.

• MCP1 or TCL1 on the short arms of chromosome 13 and 14, respectively, are implicated in the pathogenesis of T-PLL.

Clinical Features

• Presenting symptoms include fatigue, weakness, weight loss, and early satiety because of splenomegaly.

• About a third of patients have cutaneous involvement on the torso, arms, and face, which is usually present at diagnosis.

• Skin manifestations include diffuse infiltrated erythema and erythroderma, producing a nonscaling, papular, nonpruritic rash.

• Some cases present with central nervous system involvement.

Laboratory Features

• Blood lymphocyte counts often in excess of 10 × 10⁹/L at presentation.

• T-lymphocyte infiltration of the marrow is present.

• Biopsy of erythematous skin lesions can reveal a perivascular or periappendiceal dermal infiltrate of lymphoid cells, often with prolymphocyte morphology.

• Leukemia cells typically express pan-T-cell differentiation antigens (eg, CD2, CD3, CD5, and CD7), but not CD1, HLA-DR, or terminal transferase, reflecting a mature T-cell phenotype.

• In addition to pan-T-cell surface antigens, approximately:

  — Seventy-five percent of cases express CD4 (helper T-cell phenotype), but not CD8.

• Fifteen percent of cases express CD8 (suppressor/cytotoxic T-cell phenotype) but not CD4.

• Ten percent of cases express both CD4 and CD8 (less-mature T-cell phenotype).

• Leukemia cells have monoclonal T-cell receptor gene rearrangements.

Differential Diagnosis

Polyclonal T-Cell Lymphocytosis

• Cells typically are a mixture of CD4⁺/CD8^– and CD4^–/CD8⁺ T cells and lack monoclonal T-cell receptor gene rearrangements (Chap. 49).

T-Cell Large-Granular Lymphocytic Leukemia

• Leukemia cells have large granular lymphocyte morphology. (see Chap. 57)

Adult T-Cell Leukemia/Lymphoma

• This condition is endemic to the southwest of Japan and the Caribbean region. (see Chap. 66)

• Patients have lymphadenopathy, hypercalcemia, and high white blood cell counts.

• Leukemia cells have polylobed or convoluted nuclei.

• Patients typically have antibodies to HTLV-I.

Mycosis Fungoides and Sézary Syndrome

• Neoplastic cells have characteristic cerebriform nuclei. (see Chap. 65)

• This condition shares many features with T-cell PLL.

Therapy, Course, and Prognosis

• This aggressive disease is generally refractory to conventional alkylating agent chemotherapy.

• Treatment with deoxyadenosine analogues is effective in inducing complete response or partial response in about half of patients.

• Topical glucocorticoids, mechlorethamine, carmustine, ultraviolet light B, PUVA, or total skin electron beam therapy is palliative for patients with extensive cutaneous involvement (see Chap. 65).

• Clinical trials have found that alemtuzumab induced responses in more than two-thirds of heavily pretreated relapsed/refractory patients with T-cell PLL.

• Systemic glucocorticoids may be palliative.

• High-dose chemoradiotherapy and allogeneic stem cell transplantation have had anecdotal success.