Cervical cancer,Chronic lymphocytic leukemia Introduction,Chronic lymphocytic leukemia,Chronic lymphocytic leukemia Symptoms and signs,Chronic lymphocytic leukemia Diagnosis,Chronic lymphocytic leukemia Pathology,Chronic lymphocytic leukemia Staging and prognostic factors,Chronic lymphocytic leukemia Treatment,
Cervical cancer
Cervical cancer is one of the more common cancers affecting women of reproductive age.
Risk factors for cervical cancer
One of the high risk factors for cervical cancer is the presence of antibodies to the human papillomavirus (the same group of viruses that cause genital warts). Although benign, the virus is believed to trigger alterations in the cells of the cervix, leading to the development of cancer. The strains of HPV linked to cervical cancer (strains 16, 18 and 31), are not the ones that cause genital warts. Women are advised to have a pap smear annually to check for precancerous cells, or other abnormalities. If cervical cancer is detected early, it can be treated without impairing fertility.
Pathology of cervical cancer
- Squamous cell carcinoma (90%)
- Adenocarcinoma (10%)
Symptoms of cervical cancer
Cervical cancer or early cervical pre-cancers often have no signs or symptoms. That's why it's important to get Pap tests regularly. If you have any of these symptoms, call your doctor right away.
- Any unusual discharge from the vagina
- Blood spots or light bleeding when you're not having your period
- Bleeding or pain during sex
Diagnosis
Diagnosis is confirmed by pathology. CT scans are helpful both in diagnosis and in staging of this disease.
Staging of cervical cancer
- Staging system for cervical cancer
Treatment
Cervical cancer can be treated with surgery and radiation in its early stages, or chemotherapy in later stages of the disease.
- Chemotherapy for cervical cancer
Chronic lymphocytic leukemia
Introduction
Chronic lymphocytic leukemia (CLL) is a disorder of morphologically mature but immunologically less mature lymphocytes and is manifested by progressive accumulation of these cells in the blood, bone marrow, and lymphatic tissues.
Incidence
CLL is the most common leukemia in adults in western countries, and it accounts for approximately 25% of all leukemias.The incidence is also age dependent, with an increase from 5.2 per 100,000 persons older than 50 years to 30.4 per 100,000 in people older than 80.
Estimated new cases and deaths from chronic lymphocytic leukemia (CLL) in the United States in 2005:
New cases: 9,730.
Deaths: 4,600.
Gender
The male to female ratio is 2:1. This trend appears to be lost with age; the male-to-female ratio is 2:1 for patients < 50 years old, compared with 1.1:1.0 for those ≥ 75 years old.
Age
CLL occurs primarily in middle-aged and elderly individuals, with increasing frequency in successive decades of life. The median age at diagnosis is 70 years.
Race and ethnicity
In the American population, the incidence of CLL is similar in different races.
Geography
The incidence is much lower in Asia (Japan, Korea, and China), Latin America, and Africa than in the United States.Chronic lymphocytic leukemia
The etiology of CLL is unclear. However, some factors associated with CLL have been identified.
CLL with a familial association tends to occur in younger age groups with subsequent generations, perhaps because of increased screening. Association with certain HLA patterns has not been consistent.
However, exposure to some chemicals used in agriculture may increase the risk of developing CLL.
Chronic lymphocytic leukemia
Genetic factors
There is a high familial risk for CLL with family members of CLL patients (2 to 7 times).CLL with a familial association tends to occur in younger age groups with subsequent generations, perhaps because of increased screening. Association with certain HLA patterns has not been consistent.
Environmental factors
There is no documented association of CLL with exposure to radiation, alkylating agents, or known leukemogenic chemicals.However, exposure to some chemicals used in agriculture may increase the risk of developing CLL.
Viral infections
No conclusive evidence of a causal relationship exists. Associations between CLL and several viruses including:- Human T-cell lymphotrophic viruses I and II (HTLV-I and HTLV-II)
- Epstein-Barr virus (EBV)
Chronic lymphocytic leukemia
Symptoms and signs
The disease usually takes an indolent course with median survival reaching up to 10 years in untreated individuals.
noted at the time of initial diagnosis of CLL in approximately 20% of cases. The liver in CLL generally is not greatly enlarged, ranging from 2 to 6 cm below the right costal margin, with a span of dullness on percussion of 10 to 16 cm. Upon palpation, the liver is usually nontender and firm, with a smooth surface.
In addition to palpably enlarged peripheral lymph nodes, liver, and spleen, virtually any other lymphoid tissue in the body may be enlarged at diagnosis, such as Waldeyer ring or the tonsils.
Autoimmune hemolytic anemia and/or thrombocytopenia can occur in patients with any stage of CLL.
AIHA is the most frequently occurring of these. Several factors indicate that antibodies against blood cell antigens are not produced by the leukemic clone. These autoantibodies are polyclonal and are usually immunoglobulin G. The severity of the autoimmune phenomenon does not necessarily correlate with the severity of CLL, and such events may develop in patients whose disease is responding to therapy with fludarabine.
Prednisone (P) is the most commonly used treatment for autoimmune complications, with high initial response rates. Relapses are not uncommon. Cyclosporin A is another effective therapy and can produce good results, even in steroid-refractory patients. The monoclonal antibodies rituximab and alemtuzumab have also been used in some patients in whom standard therapy fails and have produced responses.
Chronic lymphocytic leukemia
Asymptomatic (40%)
The usual presentation is without symptoms and lymphocytosis is only discovered on examination of the blood picture. With the use of routine blood testing, the number of CLL patients who are asymptomatic at diagnosis has increased. Some patients may remain asymptomatic for long periods of time. The disease may progress to generalized lymphadenopathy and splenomegaly. The peripheral blood picture reveals a high white cell count (usually above 100,000) that expresses absolute lymphocytosis. It may also show associated pancytopenia.
Fatigue
The most common complaint is fatigue, but this is generally not severe.
Lymph node enlargement
The most consistent abnormal finding on physical examination is lymphadenopathy. Most patients have noted painless swelling of lymph nodes, often in the cervical area (but also at times in any other lymph node-bearing site), that spontaneously waxes and wanes but does not altogether disappear. The size of enlarged nodes may be as small as a few millimeters in diameter or as large as an orange.
Characteristically, enlarged nodes in CLL are firm, rounded, discrete, nontender, and freely mobile upon palpation, although exceptions to these generalizations are encountered, particularly when nodes have grown rapidly.
Occasionally, several enlarged nodes in the same anatomic site (cervical triangle, axilla, or femora�inguinal areas) may become confluent with each other, forming large spherical lymphoid masses. New lymph nodes may appear, sometimes in places other than the usual lymph node- bearing sites, such as over the sacrum or the thorax.
Infections
Bacterial infections, such as pneumonia, are more common in patients who present with advanced-stage disease. Infections secondary to opportunistic organisms, particularly herpes zoster, may occur. An exaggerated skin reaction to a bee sting or an insect bite is frequent (Well's syndrome).
Splenomegaly (30%)
Splenomegaly may occur, but massive splenomegaly is usually only seen in patients with end-stage disease. Splenic infarction is rare. It may be palpably enlarged in 30% to 40% of cases. The extent of enlargement varies from an organ barely palpable upon deep inspiration to one so large as to occupy the entire left side of the abdomen and pelvis, to cross the midline and encroach upon the right side of the abdomen. As is the case with enlarged lymph nodes, an enlarged spleen in CLL is usually painless and upon palpation is nontender with a sharp edge and a smooth, firm surface. Painful or infarcted splenic enlargement is an unusual presenting feature for CLL.Hepatomegaly (20%)
Hepatomegaly occurs less frequently than splenomegaly. Liver Enlargement of the liver may benoted at the time of initial diagnosis of CLL in approximately 20% of cases. The liver in CLL generally is not greatly enlarged, ranging from 2 to 6 cm below the right costal margin, with a span of dullness on percussion of 10 to 16 cm. Upon palpation, the liver is usually nontender and firm, with a smooth surface.
In addition to palpably enlarged peripheral lymph nodes, liver, and spleen, virtually any other lymphoid tissue in the body may be enlarged at diagnosis, such as Waldeyer ring or the tonsils.
Organ infiltration (<5%)
Infiltration with CLL cells may occur in any organ; at the time of diagnosis, skin lesions are the most obvious, but are seen in less than 5% of cases. In contrast to lymphoma, gastrointestinal mucosal involvement is rarely seen in CLL. Similarly, meningeal leukemia is unusual in CLL at the time of initial presentation; if present, is usually seen in patients with refractory disease.B symptoms
B symptoms are quite uncommon in patients with CLL. In contrast to the situation in lymphoma, fever in the absence of infection is rare in CLL.Autoimmune hemolytic anemia and/or thrombocytopenia can occur in patients with any stage of CLL.
Autoimmune Complications
When autoantibodies are present in CLL, they are usually targeted against hematopoietic cells, resulting in AIHA, immune thrombocytopenia, immune-mediated granulocytopenia, and pure red cell aplasia.AIHA is the most frequently occurring of these. Several factors indicate that antibodies against blood cell antigens are not produced by the leukemic clone. These autoantibodies are polyclonal and are usually immunoglobulin G. The severity of the autoimmune phenomenon does not necessarily correlate with the severity of CLL, and such events may develop in patients whose disease is responding to therapy with fludarabine.
Prednisone (P) is the most commonly used treatment for autoimmune complications, with high initial response rates. Relapses are not uncommon. Cyclosporin A is another effective therapy and can produce good results, even in steroid-refractory patients. The monoclonal antibodies rituximab and alemtuzumab have also been used in some patients in whom standard therapy fails and have produced responses.
Transformation
Transformation of CLL to diffuse large cell lymphoma (Richter's syndrome) carries a poor prognosis.Chronic lymphocytic leukemia
Diagnosis
The diagnosis of chronic lymphocytic leukemia rests on the finding of an absolute lymphocytosis of more than 5,000 in the peripheral blood.
The International Workshop on CLL (IW-CLL) and the National Cancer Institute�sponsored Working Group on CLL (NCI-WG) have outlined diagnostic criteria for CLL.
Other B-cell malignancies may also present with increased circulating lymphoid cells and should be differentiated from CLL. The diseases that may be confused with CLL are prolymphocytic leukemia (PLL), the leukemic phase of non-Hodgkin's lymphoma (mantle cell lymphoma, follicular lymphoma, or splenic lymphoma with circulating villous lymphocytes), and hairy cell leukemia (HCL). Immunophenotyping is helpful in differentiating these disorders.
The lymphocyte count usually increases over time, but fluctuations in the lymphocyte counts of untreated patients may occur, particularly in the setting of infection.
Anemia (hemoglobin less than 11 g/dL) and thrombocytopenia (platelet count less than 100 x 109/L) are frequent with disease progression but occur in only a minority of patients at the time of initial diagnosis
Three types of lymphoid infiltration of the marrow can be seen in biopsy specimens:
A bone marrow biopsy examination is not required for establishing the diagnosis of CLL, but it has considerable prognostic value.
Autoimmune thrombocytopenia is usually diagnosed on the basis of a low platelet count in the presence of adequate numbers of megakaryocytes in the bone marrow. Neutropenia may also be encountered. These cytopenias may be the result of bone marrow failure due to "packed" marrow by CLL or occur as a result of an immune-mediated process or hypersplenism.
Among these findings was the recognition that some subtypes (17p and 11q) had more pronounced lymphadenopathy as well as markedly shorter time to initiate chemotherapy and shorter overall survival than did other types.
One of the most frequent changes is a deletion in 13q14 (55% of patients). Patients with 13q deletions tend to have modest or absent lymphadenopathy.
Other typical abnormalities included deletion 11q22-23 (18%), trisomy 12q13 (16%), and deletion 17p13 (7%). Patients with deletion 17p or 11q frequently have bulky adenopathy.
Expression of CD23 helps to differentiate CLL from mantle cell lymphoma, in which cells coexpress CD19 and CD5 but lack CD23. Furthermore, the monoclonal antibody FMC7 (which recognizes an epitope on CD20) rarely reacts with CLL cells but frequently stains the cells of patients with mantle cell lymphoma.
Expression of surface immunoglobulins is usually weak and is lower than in normal B lymphocytes or most other B-cell lymphomas. Expression of CD38 on the surface of CLL cells portends a significantly worse prognosis than that for patients whose cells do not express CD38.
Chronic lymphocytic leukemia
The French-American-British (FAB) classification system divides patients into three groups depending on the percentage of abnormal cells.
A small proportion of cells may be larger lymphocytes with a large, somewhat notched nucleus, lacy-appearing nuclear chromatin, and a nucleolus that may be seen. These prolymphocytes may account for a minority of the overall population of lymphocytes in B-CLL. CLL lymphocytes are described as mature-appearing cells but are, in fact, immature, both functionally and developmentally.
Most of the other conditions associated with blood lymphocytosis such as hairy cell leukemia, prolymphocytic leukemia, and large granular cell leukemia have their own characteristic morphologic features of lymphocytes, which are distinct from CLL.
Ruptured lymphocytes or "smudge" cells are commonly seen in the peripheral smear, reflecting fragility and distortion during preparation of the peripheral smear on the glass slide.
Chronic lymphocytic leukemia
Chronic lymphocytic leukemia
The International Workshop on CLL (IW-CLL) and the National Cancer Institute�sponsored Working Group on CLL (NCI-WG) have outlined diagnostic criteria for CLL.
IW-CLL Criteria
- A sustained peripheral blood lymphocyte count greater than 10 x 109/L
- A bone marrow aspirate showing greater than 30% lymphocytes
- Peripheral blood lymphocytes identified as monoclonal B cells
NCI-WG Criteria
- A peripheral blood lymphocyte count greater than 5 x 109/L, with less than 55% of the cells being atypical.
- The lymphocytes should be monoclonal B lymphocytes expressing B-cell surface antigens (CD19, CD20, CD23), low-density surface immunoglobulin (M or D), and CD5 positivity.
Other B-cell malignancies may also present with increased circulating lymphoid cells and should be differentiated from CLL. The diseases that may be confused with CLL are prolymphocytic leukemia (PLL), the leukemic phase of non-Hodgkin's lymphoma (mantle cell lymphoma, follicular lymphoma, or splenic lymphoma with circulating villous lymphocytes), and hairy cell leukemia (HCL). Immunophenotyping is helpful in differentiating these disorders.
Laboratory Findings
Blood counts
Lymphocytosis, consisting of mature lymphocytes, is almost universal. Absolute lymphocyte counts range from 5 x 109/L to 500 x 109/L. Rarely, patients with a white blood cell count of less than 5 x 109/L may be found to have CLL based on phenotyping of the lymphocytes.The lymphocyte count usually increases over time, but fluctuations in the lymphocyte counts of untreated patients may occur, particularly in the setting of infection.
The requirement that the blood lymphocytosis must be sustained to diagnose CLL was introduced to exclude those conditions in which blood lymphocyte counts return to normal after a few weeks, such as infectious mononucleosis, pertussis, and toxoplasmosis. Nowadays this is not recommended as bone marrow examination can easily exclude nonmalignant causes. Only in CLL and similar lymphoid malignancies is lymphocytosis in the blood accompanied by bone marrow lymphocytosis.
Unlike in acute myeloid leukemia, leukostasis is uncommon in CLL, probably because of the small size and pliable nature of the cells.Anemia (hemoglobin less than 11 g/dL) and thrombocytopenia (platelet count less than 100 x 109/L) are frequent with disease progression but occur in only a minority of patients at the time of initial diagnosis
Bone marrow examination
Marrow infiltration by lymphocytes varies from 30% to 100%, with normal or increased cellularity.Three types of lymphoid infiltration of the marrow can be seen in biopsy specimens:
- Nodular
- Interstitial
- Diffuse
A bone marrow biopsy examination is not required for establishing the diagnosis of CLL, but it has considerable prognostic value.
Antiglobulin test
A positive direct antiglobulin test is seen in approximately 25% of cases, but overt autoimmune hemolytic anemia (AIHA) occurs less frequently. The incidence of a positive direct antiglobulin test (Coombs') increases significantly with disease stage.Autoimmune thrombocytopenia is usually diagnosed on the basis of a low platelet count in the presence of adequate numbers of megakaryocytes in the bone marrow. Neutropenia may also be encountered. These cytopenias may be the result of bone marrow failure due to "packed" marrow by CLL or occur as a result of an immune-mediated process or hypersplenism.
Hypogammaglobulinemia
Hypogammaglobulinemia occurs in approximately 50% of patients with CLL. At diagnosis, it may be noted in fewer than 10% of patients, but its incidence increases significantly with disease progression. Usually, all three immunoglobulin classes (G, A, and M) are decreased, but in some patients only one or two may be low. Significant hypogammaglobulinemia and neutropenia result in increased susceptibility of patients with CLL to bacterial infections.Chromosomal abnormalities
Chromosomal abnormalities occur in 50%-65% of CLL patients with analyzable metaphases. Because of the low mitotic rate in CLL, traditional karyotypic methods frequently fail. Fluorescent in situ hybridization (FISH) has improved the detection of clonal genetic abnormalities in CLL patients. In a landmark study, Dohner et al evaluated 325 patients with CLL. Using a variety of fluorescent probes, they identified chromosomal aberrations in 82%.Among these findings was the recognition that some subtypes (17p and 11q) had more pronounced lymphadenopathy as well as markedly shorter time to initiate chemotherapy and shorter overall survival than did other types.
One of the most frequent changes is a deletion in 13q14 (55% of patients). Patients with 13q deletions tend to have modest or absent lymphadenopathy.
Other typical abnormalities included deletion 11q22-23 (18%), trisomy 12q13 (16%), and deletion 17p13 (7%). Patients with deletion 17p or 11q frequently have bulky adenopathy.
Prognostic importance
These chromosomal abnormalities were potent predictors of outcome with the following median survivals:- Deletion 17p, 32 months
- Deletion 11q, 79 months
- Trisomy 12, 114 months
- Deletion 13q, 133 months
- 17p abnormalities, 9 months
- 13q deletions, 92 months
Molecular abnormalities
No single gene has been implicated in the pathogenesis of CLL. However, several genetic abnormalities have biologic and/or prognostic implications.Retinoblastoma gene
The retinoblastoma 1 (rb1) gene is located in the long arm of chromosome 13, but despite the frequent abnormalities in this region, the retained RB1 allele is usually unaffected. A more telomeric region to the rb1 gene (D13S25) is frequently affected, and in at least some cases, the abnormality is homozygous, suggesting the presence of a tumor- suppressor gene in this region.Mutations of ras
Despite the frequent involvement of chromosome 12, ras mutations are uncommon in CLL.Overexpression of bcl-2
Abnormalities of the long arm of chromosome 14 frequently involve region 14q32, the site encoding for the immunoglobulin heavy-chain gene. However, gene translocations, such as t(11;14)(q13;q32) and t(14;18)(q32;q21) (which juxtapose genes bcl-1 and bcl-2 to the heavy-chain immunoglobulin gene), are relatively uncommon and should prompt consideration of alternative diagnoses (mantle cell or follicular lymphoma). Nevertheless, increased expression of bcl-2 mRNA and protein are very common in CLL. Since overexpression of bcl-2 inhibits apoptosis, it is possible that this gene participates in the pathogenesis of CLL.
Mutations in p53
Mutations in the p53 tumor- suppressor gene are seen in 15% of all patients with CLL (17p abnormality detected by FISH). These mutations are more common in patients with advanced- stage disease or transformation. Multidrug resistance gene Approximately 40% of patients with CLL have overexpression of the multidrug resistance gene (MDR1).Immunophenotyping
More than 95% of all cases have a B-cell phenotype. In these patients, CD19 and/or CD20 are essentially always coexpressed with CD5, which is expressed on T cells and a subset of normal B cells. Other markers, such as CD21 and CD22, may also be expressed.Expression of CD23 helps to differentiate CLL from mantle cell lymphoma, in which cells coexpress CD19 and CD5 but lack CD23. Furthermore, the monoclonal antibody FMC7 (which recognizes an epitope on CD20) rarely reacts with CLL cells but frequently stains the cells of patients with mantle cell lymphoma.
Expression of surface immunoglobulins is usually weak and is lower than in normal B lymphocytes or most other B-cell lymphomas. Expression of CD38 on the surface of CLL cells portends a significantly worse prognosis than that for patients whose cells do not express CD38.
Chronic lymphocytic leukemia
Pathology
Classification
In most cases, the lymphocytes are small and mature appearing, but there may be variations in cell morphology, with some lymphocytes being larger or atypical, whereas others may be plasmacytoid or cleaved or there may be prolymphocytes.The French-American-British (FAB) classification system divides patients into three groups depending on the percentage of abnormal cells.
- Typical CLL: greater than 90% of the cells are small
- CLL/PLL: 11% to 54% of the cells are prolymphocytes
- Atypical CLL: there is heterogeneous morphology, but 10% or fewer of the cells are prolymphocytes
Lymphocyte Morphology
Lymphocytes must have the morphologic appearance of normal, mature cells. These are typically uniform populations of small lymphocytes (median volume 211.5 femtoliter). The nucleus virtually fills the cell, leaving only a thin rim of visible cytoplasm. The nuclear chromatin is clumped, and a nucleolus is usually not discernible.A small proportion of cells may be larger lymphocytes with a large, somewhat notched nucleus, lacy-appearing nuclear chromatin, and a nucleolus that may be seen. These prolymphocytes may account for a minority of the overall population of lymphocytes in B-CLL. CLL lymphocytes are described as mature-appearing cells but are, in fact, immature, both functionally and developmentally.
Most of the other conditions associated with blood lymphocytosis such as hairy cell leukemia, prolymphocytic leukemia, and large granular cell leukemia have their own characteristic morphologic features of lymphocytes, which are distinct from CLL.
Ruptured lymphocytes or "smudge" cells are commonly seen in the peripheral smear, reflecting fragility and distortion during preparation of the peripheral smear on the glass slide.
Chronic lymphocytic leukemia
Staging and prognostic factors
Staging of CLL
Prognostic factors
- Beta-2 microglobulin elevation (higher levels imply a worse prognosis).
- Diffuse pathology on bone marrow.
- Lymph in blood of more than 50,000.
- Lymphocyte morphology of more than 5% prolymphocytes.
- Short lymphocyte doubling time of less than 1 year.
- Multiple and complex karyotypes.
- Expression of T-cell markers (CD4 and CD7).
- Stage (see Rai staging system and Binet classification).
- Lymphocyte doubling time (doubling of the white blood cell count in excess of 1 year implies a favorable prognosis).
Immunoglobulin variable region heavy chain gene (IgVH) mutation
This test is very labor intensive and not available as yet for general clinical use. Prognostic marker surrogates are being evaluated.- The finding of significant numbers of mutations in this region is associated with a median survival in excess of 20 to 25 years.
- The absence of mutations is associated with a median survival of 8 to 10 years.
ZAP-70
This test, which is commercially available, but has not undergone national standardization, has been proposed as a surrogate for the mutational status.- ZAP-70 positivity (>30%) correlates with a more unfavorable median survival (6-10 years), while a negative ZAP-70 correlates with a median survival of more than 15 years.
Chromosomal abnormalities by fluorescent in situ hybridization
- 13q- is favorable (with a 91% 2-year survival in a retrospective trial).
- 17p-, 11q-, trisomy 12, and 6q- have unfavorable prognoses (with 67% to 75% 2-year survival in a retrospective trial).
CD38 immunophenotype
CD38 positivity (>30%) correlates with a worse prognosis, but there is a 30% false-positive rate and a 50% false-negative rate using IgVH mutational status as the gold standard for prognosis.Chronic lymphocytic leukemia
Treatment
Treatment options include watch and wait if there are no symptoms and the patient does not have anemia or thrombocytopenia (i.e. the patient is in stage I or stage II) and doesn't have any of the poor prognostic factors. Many chemotherapeutic agents such as chlorambucil, steroids, cyclophosphamide, fludarabine. Resistant cases are usually treated with a fludarabine containing regimen (FND) if not taken previously or CVP or CHOP. Monoclonal antibodies such as Rituximab and CAMPATH-1H can be used in resistant forms not responding to the treatment above.
Bone marrow transplantation for CLL are under investigation for all stages of the disease. Currently it can be offered to patients with refractory CLL.
Local radiotherapy may be required for local control of symptoms related to enlarged lymph nodes and splenomegaly.
A meta-analysis of 6 trials of immediate versus deferred therapy with chlorambucil (including the aforementioned trial by the French Cooperative Group) showed no difference in overall survival at 10 years.
Chlorambucil is frequently combined with oral prednisone (30-100 mg/m2/d), although there is no clear evidence that the combination improves responses or overall survival over chlorambucil alone. Prednisone is of value, however, in the management of autoimmune cytopenias.
COP and CHOP Various drug combinations have been used in CLL, mostly in patients with advanced-stage disease. The most frequently employed combinations have been COP and these three drugs plus doxorubicin (CHOP). The dose of doxorubicin used is usually low (25 mg/m2). A higher dose of doxorubicin (50 mg/m2) has been employed in some regimens, such as CAP (cyclophosphamide, doxorubicin [Adriamycin], and prednisone).
Rituximab also has been investigated and is active both as a single agent and in combination with chemotherapy. Because of rituximab�s efficacy without significant toxicity, it is assuming a greater role in the treatment of patients with CLL. Other antibodies, including lumiliximab (anti-CD23) and HuD10, are currently in early-phase testing.
The standard-dose of rituximab is 375 mg/m2 weekly x 4.
Using a sequential approach with these two agents, the group at Memorial Sloan-Kettering Cancer Center has shown that consolidation therapy with high-dose cyclophosphamide markedly improves the frequency of a CR over fludarabine alone.
BMT using nonablative conditioning regimens has produced encouraging results and should be considered in the setting of a clinical trial, particularly for patients > 60 years.
Transformation of CLL to diffuse large cell lymphoma (Richter's syndrome) carries a poor prognosis with a median survival of less than 1 year, although 20% of the patients may live more than 5 years after aggressive combination chemotherapy.
Expression of T cell markers and those that have clonal rearrangements of their T-cell receptor genes have a shorter median survival (13 months) with minimal responses to chemotherapy.
Bone marrow transplantation for CLL are under investigation for all stages of the disease. Currently it can be offered to patients with refractory CLL.
Local radiotherapy may be required for local control of symptoms related to enlarged lymph nodes and splenomegaly.
Stage 0
Because of the indolent nature of stage 0 chronic lymphocytic leukemia, treatment is not indicated.Rationale
The French Cooperative Group on Chronic Lymphocytic Leukemia randomized 1,535 patients with previously untreated stage A disease to receive either chlorambucil or no immediate treatment and found no survival advantage for immediate treatment with chlorambucil.A meta-analysis of 6 trials of immediate versus deferred therapy with chlorambucil (including the aforementioned trial by the French Cooperative Group) showed no difference in overall survival at 10 years.
Stage I, II, III, and IV
Since patients with early-stage CLL have a good long-term prognosis, and early therapy has not changed the outcome of the disease, patients in the early stages should not be treated unless specific indications exist.Indications for treatment
The NCI-WG guidelines are recommended for patients being entered on clinical research protocols and also serve as useful guides for treatment in clinical practice.
The NCI-WG indications to initiate treatment for CLL include:- Constitutional symptoms attributable to CLL: weight loss (greater than 10% of baseline weight within the preceding 6 months), extreme fatigue, Eastern Cooperative Oncology Group performance status of 2 or greater, fever (temperature greater than 38�C or 100.5�F for at least 2 weeks), or night sweats without evidence of infection
- Progressive bone marrow failure characterized by the development of, or worsening of, anemia or thrombocytopenia, or both
- Splenomegaly that is massive (greater than 6 cm below the left costal margin) or progressive
- Lymphadenopathy that is massive (greater than 10 cm in longest diameter) or progressive
Progressive lymphocytosis defined as an increase in the absolute lymphocyte count by greater than 50% over a 2-month period, or a doubling time predicted to be less than 6 months- AIHA or autoimmune thrombocytopenia, or both, poorly responsive to corticosteroid therapy
Hypogammaglobulinemia or monoclonal gammopathy is not a sufficient criterion to initiate therapy
Response criteria
| NCI-WG Response Criteria for Chronic Lymphocytic Leukemia | ||
| Parameter | CR | PR |
| Lymphocytes | ≤4000/ �L | ≥50% decrease |
| Lymph nodes (liver, spleen) | No palpable disease | ≥50% decrease |
| Neutrophils | ≥1500/ �L | ≥1500/ �L or ≥50% improvement |
| Platelets | >100,000/ �L | >100,000/ �L or ≥50% improvement |
| Hemoglobin | >11 g/dL (untransfused) | >11 g/dL or ≥50% improvement |
| Bone marrow | <30% lymphocytes, no nodules | NA |
| Symptomatology | None | Variable |
Chemotherapy
1. Chlorambucil
The most frequently used single agent for CLL is chlorambucil, given as either 0.1 mg/kg daily or 20-40 mg/m2 every 2-4 weeks. Therapy is continued until the signs or symptoms requiring therapy are controlled.Chlorambucil is frequently combined with oral prednisone (30-100 mg/m2/d), although there is no clear evidence that the combination improves responses or overall survival over chlorambucil alone. Prednisone is of value, however, in the management of autoimmune cytopenias.
2. Cyclophosphamide
Cyclophosphamide (Cytoxan, Neosar) is an alternative to chlorambucil. The usual dose is 0.5-1 g/m2 every 3-4 weeks together with vincristine and steroids (eg, COP [cyclophosphamide, vincristine (Oncovin), and prednisone] regimen).Rationale
- Overall response rate with either chlorambucil or cyclophosphamide is approximately 40% to 60%, with 3% to 5% CR.
3. Fludarabine
Fludarabine (Fludara), now perhaps the drug of choice for treating CLL, has been demonstrated in a randomized trial to be more active than chlorambucil for the treatment of CLL. Fludarabine is a nucleoside analog.
Fludarabine is given at a dose of 25-30 mg/m2/d for 5 days every 3-4 weeks.Rationale
- In previously untreated patients, the response rate was 63%-80%, with 8%-35% of patients achieving a CR.
- A large randomized study comparing fludarabine, CAP, and CHOP demonstrated an increased response rate with fludarabine but no difference in survival. Randomized trials of fludarabine vs chlorambucil in previously untreated patients showed improvements in response rate (overall and CR), duration of response, and disease progression-free survival with fludarabine but no survival advantage.
4. COP and CHOP
A meta-analysis of 10 trials comparing combination chemotherapy before the availability of rituximab to chlorambucil alone showed no difference in overall survival at 5 years.COP and CHOP Various drug combinations have been used in CLL, mostly in patients with advanced-stage disease. The most frequently employed combinations have been COP and these three drugs plus doxorubicin (CHOP). The dose of doxorubicin used is usually low (25 mg/m2). A higher dose of doxorubicin (50 mg/m2) has been employed in some regimens, such as CAP (cyclophosphamide, doxorubicin [Adriamycin], and prednisone).
Rationale
- Response rates have been 40%-85% with these combinations. In randomized studies, COP was no better than chlorambucil plus prednisone. Although CHOP initially achieved better survival than COP (in patients with Binet stage C disease) or chlorambucil plus prednisone, longer follow-up has not confirmed this survival advantage.
5. Rituximab
Rituximab has been used as initial therapy for patients with CLL. It was given in the standard dose of 375mg/m2 weekly for weeks followed by maintenance rituximab was given weekly x 4 every 6 months for 2 years.- The response rate at 6 weeks was 51%, with 4% complete remission. The median progression-free survival was 18.6 months.
6. Alemtuzumab
Alemtuzumab (campath-1H), the monoclonal antibody directed at CD52, is under clinical evaluation for first-line use alone or in combination therapy.Refractory CLL
1. COP and CHOP
COP therapy is often used in patients who had previously been treated with alkylating agents and had become refractory to the therapy.
A retrospective study showed that the overall response rate to COP was 25%. The median duration of responses was 18 months.
2. Fludarabine
Fludarabine (Fludara), is also useful in refractory CLL. Fludarabine is given at a dose of 25-30 mg/m2/d for 5 days every 3-4 weeks.
Rationale
- When given to previously treated patients this nucleoside analog produced responses in 20%-50% of patients, with 5%-15% of patients achieving a complete response (CR) and an additional 5%-20%, a �nodular partial response (PR),� ie, a CR but with the presence of lymphoid nodules in the bone marrow.
3. Cladribine
Cladribine (2-chlorodeoxyadenosine, 2-CdA [Leustatin]) is also active in CLL when given at doses of 0.1 mg/kg/d (or 4 mg/m2/d) for 7 days. At therapeutic doses, this agent appears to be associated with more myelosuppression, particularly thrombocytopenia, than fludarabine. This finding limits its utility in treating CLL, but a direct comparison with fludarabine has not been reported.4. Pentostatin
The third purine analog active against CLL is pentostatin (Nipent). Previously, toxicity limited its use as an antineoplastic agent. More recently, the recognition that safe use of this drug requires concomitant hydration and close attention to renal function (it is both toxic to and cleared by the kidneys) has renewed interest in clinical evaluation with this agent. Preliminary studies of pentostatin combined with cyclophosphamide demonstrate responses in > 70% of previously treated patients (including those whose disease is refractory to fludarabine) with acceptable toxicity.5. Rituximab
Rituximab, an anti-CD20 monoclonal antibody. When used alone, higher doses of rituximab or increased frequency or duration of therapy is required for comparable responses to those seen for other indolent lymphomas.Rituximab also has been investigated and is active both as a single agent and in combination with chemotherapy. Because of rituximab�s efficacy without significant toxicity, it is assuming a greater role in the treatment of patients with CLL. Other antibodies, including lumiliximab (anti-CD23) and HuD10, are currently in early-phase testing.
The standard-dose of rituximab is 375 mg/m2 weekly x 4.
- Standard-dose rituximab induces responses in up to 30% of previously treated patients; all responses are partial. A dose-escalation study using doses of 500 mg/m2 to 2250 mg/m2 in 50 patients with lymphoid malignancies produced an OR rate of 40%; all of the responses were PRs.
4. Alemtuzumab
Alemtuzumab (campath-1H) has been approved by the FDA for the treatment of refractory CLL. The subcutaneous route of delivery is preferred to the intravenous route to avoid acute allergic reactions. Profound and long-lasting immunosuppression has been seen, which mandates monitoring for reactivation of cytomegalovirus and prophylaxis for pneumocystis and herpes virus infections.- Alemtuzumab has produced a response rate of 44% in patients with heavily pretreated CLL. In a recent pivotal trial in patients with fludarabine-refractory disease, alemtuzumab resulted in an overall response rate of 33%.
5. Fludarabine combinations
1. Fludarabine - chlorambucil
The addition of prednisone or chlorambucil to fludarabine therapy did not improve the response rate and is associated with an increased incidence of opportunistic infections and other toxicities.2. Fludarabine - cyclophosphamide
The combination of fludarabine (30 mg/m2/d for 3 days) and cyclophosphamide (300 mg/m2/d for 3 days) has resulted in an improved response (overall and CR) rate vs fludarabine alone. Longer followup is needed to assess the effect of this combination on survival.Using a sequential approach with these two agents, the group at Memorial Sloan-Kettering Cancer Center has shown that consolidation therapy with high-dose cyclophosphamide markedly improves the frequency of a CR over fludarabine alone.
3. Fludarabine - rituximab
Recent data suggest that the addition of a monoclonal antibody to fludarabine based therapy may markedly improve CR rates in this disease. A study conducted by the Cancer and Leukemia Group B (CALGB) randomized patients with previously untreated CLL to receive fludarabine or a combination of fludarabine and the anti-CD20 antibody rituximab (Rituxan) at standard doses. Patients in both arms subsequently received a consolidation course of rituximab for 4 weeks.
Overall response rates were high in both arms, but there was a significantly higher CR rate (33%) in the concurrent arm than in the arm with fludarabine alone (15%). The CR rate increased in both groups after consolidation therapy with rituximab. (CALGB)
4. Fludarabine - alemtuzumab
Kennedy et al combined alemtuzumab (Campath), a humanized monoclonal antibody targeting the panlymphocyte antigen CD52, with fludarabine in six patients whose disease was refractory to each agent used singly. There were five responses, including one CR. The authors noted that the observed responses were better than the prior response after each agent used singly.6. Bone marrow transplantation
Both allogeneic and autologous bone marrow transplantation (BMT) have been tested in patients with CLL.Allogeneic BMT
Allogeneic BMT is a viable option for younger patients with CLL, particularly if they have not responded to alkylating-agent and/or nucleoside-analog therapy and are in an advanced stage of disease.- The series reported to date, including a majority of patients with advanced, refractory disease, has documented a CR rate in excess of 70%. The response is sustained in most patients, although follow-up is still short.
BMT using nonablative conditioning regimens has produced encouraging results and should be considered in the setting of a clinical trial, particularly for patients > 60 years.
Autologous BMT
Since the median age of patients with CLL is usually higher than the age considered acceptable for allogeneic BMT, autologous transplants using purged marrow have also been investigated. In general, results have been disappointing, with the best results seen in patients with responsive disease and low tumor burdens, a group that might have fared well without a transplant.7. Splenectomy
Splenectomy may be beneficial for patients in whom hypersplenism is the cause of cytopenias (particularly in patients without significant lymphadenopathy) or for palliation when splenomegaly is symptomatic and refractory to chemotherapy. Cytopenias frequently respond to splenectomy. Perioperative mortality varies widely and is largely related to the experience of the surgeon in performing splenectomy in these patients. In experienced hands, spelenctomy can be performed with minimal mortality, even in patients with end-stage disease.8. Involved-field radiation therapy
Relatively low doses of radiation will effect an excellent response for months or years. Sometimes radiation of one nodal area or the spleen will result in abscopal effect (i.e., the shrinkage of lymph node tumors in untreated sites).Prognosis and survival
The overall 5-year survival is approximately 60%, but depends on stage of disease.Transformation of CLL to diffuse large cell lymphoma (Richter's syndrome) carries a poor prognosis with a median survival of less than 1 year, although 20% of the patients may live more than 5 years after aggressive combination chemotherapy.
Expression of T cell markers and those that have clonal rearrangements of their T-cell receptor genes have a shorter median survival (13 months) with minimal responses to chemotherapy.
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