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Wednesday, April 11, 2012

Leukemia (specific information)

Author: Dr Frederick Appelbaum Fred Hutchinson Cancer Research Center Seattle 2008-07-28

Contents:
Acute Myeloid Leukemia (AML)
Acute Promyelocytic Leukemia (APL)
Acute Lymphocytic Leukemia (ALL)
Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL)

Acute Myeloid Leukemia (AML)


Background

AML is the most common of the four types of leukemia, with an estimated 12,000 new cases diagnosed in the United States in 2006.  AML may occur at any age, but the incidence of the disease increases as individuals get older, with the average age at diagnosis being approximately 60 years.  If untreated, the average survival of patients is approximately 2 months, but with appropriate treatment, many patients can now be cured of their disease.   

Biology and Classification

Like other forms of leukemia, AML is caused by alterations in the genes of an early blood forming cell causing excess growth and decreased maturation of the cell and its progeny.  In many cases of AML, the genetic alternation can be identified either by cytogenetic testing or by other molecular tests.  Cytogenetic and molecular testing of AML are the most important tests for determining the correct form of therapy and are performed on a bone marrow specimen. The most important chromosomal abnormalities in AML are listed in Table 1 along with their incidence and implications. 


Table 1    Common Cytogenetic Abnormalities in AML
 
Abnormality Incidence Significance
t(8;21) 6% Favorable risk
inv(16) 5% Favorable risk
t(15;17) 10% APL, favorable risk, different treatment
11q23 5% Intermediate risk
-7/-7q 7% Unfavorable risk
-5/-5q 4% Unfavorable risk
 
 
Additional testing may reveal mutations in key genes that can’t be identified by routine cytogenetic testing. The two most important in AML are abnormalities of a gene called “FLT3” and a gene called “NPM1”.  Mutations in FLT3 are seen in approximately 30% of cases, while mutations in NPM1 occur with a similar frequency.
Although cytogenetic and molecular testing are by far the most important methods of classifying AML, historically physicians also classified AML by how it looks under a microscope, using the so-called “FAB” (French-American-British) system that divided AML into 8 classes from M0 to M7.  While this nomenclature is still sometimes used, it is of little clinical or scientific significance.

Causes of AML 

In the vast majority of cases of AML, no reason can be found for the mutational events that result in the disease.  Patients with Down syndrome, Fanconi anemia and a few other uncommon genetic diseases have an increased incidence of AML. Patients treated with chemotherapy and radiation therapy for other malignancy are at increased risk as well.  Exposure to tobacco smoke and benzene has been linked to a greater chance for the development of AML. Although in the large majority of cases AML is not hereditary, there are rare families that carry a gene that increases susceptibility to AML.  AML is not contagious.

Signs and Symptoms of AML 

The most common signs and symptoms of AML are due to the lack of normal marrow function. Lack of red cell production causes anemia, which results in pallor, headache, fatigue, shortness of breath with exertion, and dizziness. The lack of normal functioning white cells leads to recurrent infections, and a lack of platelets leads to easy bruising, gum bleeding and petechiae. Leukemic blasts may accumulate in the gums causing swelling, in the skin causing multiple small raised lesions, or in the liver and spleen leading to enlargement of these organs and vague discomfort in the right and left upper abdomen. The symptoms of AML generally develop over a period of several weeks, but slower or more rapid onset is sometimes seen.

Diagnosis of AML

The diagnosis of AML is usually first suggested by the finding of an abnormality in the number or appearance of peripheral blood cells.  Confirmation of the diagnosis usually requires examination of the bone marrow.

Treatment of AML

Once AML is diagnosed, it is important to begin treatment relatively promptly.  In some cases, AML may evolve more slowly and a delay in therapy of some days or even weeks is possible, but in most cases, AML evolves rapidly, and a delay of even a few days can be dangerous.  Because of differences in treatment approaches, the following discussion is separated into three major sections – treatment for AML in patients less than age 60, treatment for patients over age 60, and treatment of acute promyelocytic leukemia.


Treatment of AML in Patients Less than Age 60


      Remission Induction
Without treatment, AML is generally fatal in an average of about 2 months.  The first goal of therapy is to obtain a complete remission of the disease.  A complete remission (abbreviated as CR),  is defined as elimination of all leukemic blasts from the peripheral blood, reduction in the blast count in the marrow to less than 5%, and recovery of marrow cell function so that peripheral red, white and platelet counts recover to normal levels.  Standard initial therapy of AML involves the administration of a combination of two chemotherapeutic agents, cytarabine and an anthracycline (usually either daunomycin or idarubicin).  Various doses and schedules of these two agents have been studied, and sometimes additional agents are added, but there is as yet little evidence that one combination is superior to all others.  A commonly used approach is daunomycin 60 mg/m2 i.v. on days 1, 2 and 3, along with cytarabine 200 mg/m2 i.v. on days 1-7.  Patients are usually hospitalized when these agents are given. The chemotherapeutic agents preferentially kill leukemia cells, but also affect normal cells, so that shortly after therapy, most patients will develop a profound drop in their normal blood counts, making them susceptible to bleeding and infection, they may loose their hair and may develop sores in their mouth (oral mucositis).  These side effects are temporary, and if the therapy is successful, within two or three weeks of starting chemotherapy mouth sores heal, counts begin to recover, and a remission is achieved.  In order to document a remission, a repeat bone marrow is required.  If leukemia blasts persist in the bone marrow, a second round of induction may be needed.  With standard chemotherapy, approximately 75% of patients less than age 60 will achieve a complete remission.  Approximately 10% may die of infection, bleeding or other complications during the induction attempt and in 15% of cases, the leukemia will persist despite chemotherapy. 
Achievement of a complete remission is not synonymous with cure, and if further therapy is not given, the leukemia will regrow in virtually every case. Thus, some form of post-induction therapy is required.

      Post-induction Therapy

There are three forms of post-induction therapy that are commonly used in patients less than age 60 with AML in first remission – further chemotherapy, allogeneic hematopoietic cell transplantation (HCT) or autologous HCT.  The therapy of choice is influenced by the subtype of leukemia, the availability of an appropriate donor and patient and physician choice.
Standard post transplant chemotherapy generally involves administering three or four cycles of chemotherapy very similar to that used for initial induction chemotherapy.  There is evidence that the use of higher doses of cytarabine during consolidation is of some advantage. [1]  With standard consolidation chemotherapy, approximately 40% of patients with AML who achieved a first remission can expect to be cured. The leukemia will recur (or relapse) in the remainder. The vast majority of relapses occur anytime within 3 years of diagnosis. 
Approximately 30% of patients will have a brother or sister who is HLA matched with them.  HLA is a marker found on white cells that determines whether a hematopoietic cell transplant is possible or not.  Hematopoietic cell transplantation involves treating the patient with very high dose chemotherapy or chemo-radiotherapy and transplanting hematopoietic stem cells obtained from the bone marrow or peripheral blood of the matched sibling.  The procedure is complex but results in cure in approximately 60-65% of patients with AML transplanted in first remission. Approximately 20-25% may die of the procedure, while relapse can still occur in 10-20%. 
Autologous HCT involves collecting hematopoietic stem cells from the bone marrow or peripheral blood of the patient and freezing them.  The patient is then treated with very high dose chemotherapy or chemo-radiotherapy, following which the stem cells are reinfused. 
A number of prospective randomized trials have been conducted comparing chemotherapy versus allogeneic transplantation versus autologous transplantation for patients with AML in first remission. Because results have been somewhat inconsistent, investigators have performed “meta-analyses” of these studies, a process in which the results of many studies are combined.  The most recent meta-analyses show that there is a survival advantage for allogeneic HCT compared to chemotherapy or autologous transplantation. [2, 3]  However, the relative benefits of allogeneic transplantation depend on the subtype of leukemia, with no advantage seen for patients with favorable risk disease, only a modest benefit for patients with intermediate risk disease and considerable benefit for patients with unfavorable risk disease. [4]  Some investigations suggest that the intermediate risk patients can be further subdivided into two groups – those with mutations in the NPM1 gene but without mutations in FLT3, who do almost as well as the favorable risk patients, and the remainder who do not have as favorable a prognosis. [5] 

Recurrent Disease

Patients who recur with AML after initial therapy can sometimes achieve a second remission with further chemotherapy.  Because the prospects for cure with further chemotherapy are poor, HCT should be strongly considered if the patient did not have a transplant as part of their initial therapy.


Treatment of AML in Patients Age 60 or Older

      Remission Induction
 
AML in older patients is more difficult to treat for two reasons. [6] Older patients often have other illnesses that make it harder for them to tolerate the toxic effects of chemotherapy.  Further, for reasons that are not well understood, AML in older individuals is less sensitive to chemotherapy.  An initial decision that must be made in considering treatment in the older patient is whether exposure to standard induction chemotherapy is likely to benefit the patient.  For patients over age 70 or 75, and particularly those with other significant illnesses (such as heart failure, renal failure or chronic obstructive lung disease), intensive induction chemotherapy may cause more harm than good, and many physicians will choose to treat such patients with low-dose cytarabine, or withhold chemotherapy and treat with antibiotics and transfusion support. [6]  For patients age 60-75 who are otherwise healthy, standard chemotherapy can be expected to result in complete remission in 40-65% of cases, depending on other risk factors.

      Post-induction Therapy

As in the case of younger patients, some form of therapy is warranted in older patients who have achieved a complete remission.  However, older patients may have difficulty tolerating high dose cytarabine, and so most physicians will chose several cycles of less intensive chemotherapy as post-induction therapy.

Acute Promyelocytic Leukemia (APL)



Background


APL is a distinct subtype of AML accounting for about 8% of cases.  Patients with APL tend to be younger on average than other AML patients and are more often Hispanic. At the time of diagnosis, patients virtually always present with some evidence of a coagulation disorder, with easy bruising, petechiae or overt bleeding.  A unique chromosomal translocation, t(15;17), is found in virtually every case of APL. Because of its unique clinical characteristics and response to specific agents, APL is treated differently from all other forms of leukemia.

Induction Therapy

APL is uniquely sensitive to two chemotherapeutic agents, all-trans retinoic acid (ATRA) and arsenic trioxide.  Clinical trials have shown that induction chemotherapy that includes ATRA and an anthracycline (daunomycin or idarubicin) is the preferred approach, and with these combinations, complete response can be expected in approximately 90% of patients. [7]  Response rates tend to be higher in those patients presenting with a white count less than 10,000/mm3Occasionally patients receiving ATRA will develop fever, shortness of breath and abnormalities on chest X-ray. These can be manifestations of the so-called retinoic acid syndrome, which usually responds quickly to treatment with high-dose steroids.

 


Post Remission Therapy

Patients with APL who achieve an initial remission are treated with several cycles of consolidation chemotherapy, usually using agents similar to those used during induction.  Randomized trials suggest that use of maintenance chemotherapy with ATRA alone or combined with other agents for some period following consolidation (often up to a year) is of further benefit. [8]  With contemporary induction, consolidation and maintenance regimens, approximately 60-70% of patients with APL are cured.  Because chemotherapy is so successful in APL, there is no role for transplantation while patients are in first remission.

Recurrent Disease

Arsenic trioxide is a very effective agent for the treatment of recurrent APL; approximately 80-90% of patients who relapse after initial therapy for APL will achieve a second remission if treated with arsenic trioxide (assuming they have not previously been treated with the drug). [9] Arsenic trioxide can cause cardiac abnormalities and symptoms similar to those of the ATRA syndrome, and so should be administered by individuals with experience in its use. Once patients achieve a second remission, consideration should be given to pursuing an HCT.
 

Acute Lymphocytic Leukemia (ALL) 

ALL is less common than AML, occurring in an estimated 4000 persons in the United States in 2006.  It is the most common form of leukemia in childhood, following which the incidence drops until the age of 45, when the incidence begins to increase.  Like AML, ALL is rapidly fatal if untreated. With appropriate treatment, most children with ALL can be cured of their disease.

Biology and Classification

As in AML, cytogenetic abnormalities are found in the majority of cases of ALL.  These are listed in Table 2 along with their incidence and implications.  Immunophenotyping is also of use in the diagnosis and classification of ALL; most cases have B-cell markers on their surface, but up to 25% will have T-cell markers.  The distinction between B-cell and T-cell ALL may be of some importance in the selection of therapies. ALL is sometimes classified by its appearance into three subgroups, L1, L2 and L3.  However, after accounting for molecular and immunologic findings, classification by morphology is of little clinical or scientific use.

Table 2    Common Cytogenetic Abnormalities in ALL
Abnormality
Incidence
Significance
9p-
9%
Favorable risk
6q-
7%
Intermediate risk
t(4;11)
7%
Unfavorable risk
t(9;22)
19%
Unfavorable risk, different treatment

    


Causes of ALL

As for AML, in the vast majority of cases of ALL, no cause can be found.  Prior exposure to radiation used to treat other diseases increases the risks of development of ALL.  Very few other associations have been discovered, despite intensive investigations.  ALL is not hereditary, nor is it contagious.

Signs and Symptoms of ALL

The majority of signs and symptoms of ALL are due to failure of normal marrow function. Patients with ALL fail to make sufficient red cells and so are anemic, resulting in pallor, fatigue, headache, shortness of breath or a racing pulse with exertion, and dizziness upon standing.  A lack of normal white cell production can lead to recurrent infections causing fever, night sweats or non-healing skin sores.  Insufficient platelet production can result in easy bruising, petechiae, gum bleeding or prolonged bleeding from minor cuts. Other signs of ALL can be the result of the growth and infiltration of the leukemic cells themselves leading to diffuse boney aches, enlarged tonsils or swollen lymph nodes. 

Diagnosis of ALL

The diagnosis of ALL is usually first suggested by a complete blood count with an abnormality in the number or appearance of cells. Confirmation of the diagnosis requires a bone marrow examination.  ALL sometimes infiltrates into the central nervous system (CNS) and can be found in the fluid around the brain (the cerebrospinal fluid).  Thus, a spinal tap is frequently performed during initial evaluation to determine if there is CNS involvement, which can influence subsequent therapy.

Treatment of ALL

Without treatment, ALL is a rapidly fatal disease, and so once the diagnosis is made, treatment should be begun as soon as possible. The type of treatment is influenced by patient age, extent of disease (for example, whether it has spread to the CNS), and the cytogenetic and molecular profile of the disease.


Induction Chemotherapy

The initial goal of treatment of ALL is to induce a complete remission.  Various drug regimens have been tested, and the most active generally include some combination of vincristine, prednisone, asparaginase, anthracyclines, and cyclophosphamide.  There is currently insufficient evidence to state that any one regimen is superior to all others.  There are several types of ALL where alternative regimens are often used.  In patients with ALL with the Philadelphia chromosome (which is a specific translocation between chromosomes 9 and 22), adding imatinib, dasatinib, or nilotinib to the chemotherapy may be of benefit. [10]  In patients with mature B-cell ALL (Burkitt’s leukemia), rituximab is often added to the initial chemotherapy. [11]  Patients are usually hospitalized while receiving induction chemotherapy.  Within days of starting therapy, most patients will have a severe drop in their red cell, white cell, and platelet counts.  Patients then receive antibiotic and transfusion support until their blood counts recover, which can take several weeks, depending on the particular regimen used for initial treatment.  With currently used regimens, complete responses are expected in approximately 85% of adults and 95% of children. 


Post-induction Therapy

There are three general forms of post-induction therapy for ALL: further chemotherapy, allogeneic HCT and autologous HCT.  The choice of therapy is influenced by the age of the patient, the subtype of leukemia, the availability of an appropriate donor, and many other issues including the underlying health of the patient as well as the patient's treatment goals. 
Most children with ALL can be cured using a combination of consolidation chemotherapy, central nervous system treatment, and maintenance therapy.  There are a number of different treatment regimens that have been successfully employed. In most, consolidation chemotherapy is made up of several cycles of chemotherapy similar in intensity to initial induction chemotherapy and which are composed of some of the same drugs used during induction, but often with others included as well.  Chemotherapeutic agents given orally or intravenously do not penetrate well into the central nervous system because of a “blood/brain barrier.” Even if patients do not have central nervous system involvement at diagnosis, disease recurrence in the CNS will occur in up to one third of patients unless specific measures are taken to prevent this.  Such CNS prophylaxis may include cranial irradiation, direct injection of chemotherapy into the cerebrospinal fluid via a lumbar tap, or intravenous administration of specific chemotherapies at very high doses, which causes then to cross into the CNS.  Some form of CNS prophylaxis is used in virtually every ALL treatment protocol.  Following consolidation chemotherapy and CNS prophylaxis, patients are generally treated with low dose maintenance chemotherapy for anywhere from 1 to 3 years, depending on patient risk factors and the particular treatment regimen chosen.  Some children with very high risk ALL, as determined by cytogenetic tests showing t(9;22) or t(4:11), may benefit from allogeneic transplantation while in first remission. [12]
Post-remission therapy for adults age 17-60 may include many of the same elements as described for children, including consolidation chemotherapy, CNS prophylaxis and maintenance chemotherapy.  However, even though the same therapies are used, cure rates of adult ALL are lower than seen in children, averaging around 40%.  For this reason, studies have been conducted comparing standard chemotherapy with allogeneic or autologous transplantation.  Allogeneic transplantation appears to offer a survival advantage, particularly for high risk patients as determined by cytogenetic risk grouping.  There is little evidence to suggest that autologous transplantation in first remission is of benefit.

Relapsed or Refractory ALL     

Children with ALL whose disease recurs more than 18 months after treatment has ended can often be cured by retreatment with chemotherapy similar to that used for first line treatment.  Children with early recurring disease and adults with relapsed ALL often respond to second line chemotherapy, but most of these responses are temporary. There is no single regimen that has been shown to be superior for recurrent ALL.  Clofarabine has recently been approved by the FDA for this indication; nelarabine has also recently been approved for treatment of recurrent T-cell ALL.   Because responses to retreatment are only temporary, patients with recurrent disease are often treated with allogeneic transplantation if they were not transplanted in first remission and if an appropriate donor can be identified.                   


Chronic Myeloid Leukemia (CML)


Background

Chronic myeloid (or myelogenous) leukemia developed in approximately 4500 Americans in 2006.  Although it is sometimes seen in childhood, the incidence of the disease increases with age and the median age of diagnosis is around 60 years.

Biology and Classification

A specific chromosomal translocation, t(9;22), gives rise to CML. This translocation involves the movement of a small part of chromosome 9 to chromosome 22, and the reciprocal movement of a piece of chromosome 22 to chromosome 9. The abnormal chromosome 22 with the added piece of 9 is called the “Philadelphia chromosome”, based on the city where it was first described. The break in chromosome 9 occurs within a gene called “ABL”, while the break in chromosome 22 occurs in the gene called “BCR.”  A result of the translocation is the creation of a new gene that is a fusion of BCR and ABL. The product of the fusion gene is what causes the abnormal cell growth. The exact site of the breaks within chromosome 9 and 22 can alter the function of the fusion gene; thus, t(9:22) is also associated with ALL, but the breakpoints in ALL and CML frequently differ.
                                         
CML generally occurs in three phases: chronic phase, accelerated phase, and blast crisis.  Chronic phase CML is characterized by a slow increase in the number of mature-appearing granulocytes in the bone marrow, peripheral blood, and often, the liver and the spleen.  Even with no treatment patients may live for several years with chronic phase CML with few, if any, symptoms.  However, if untreated, after some period of time the disease will enter an accelerated phase during which the rate of white cell increase accelerates, normal blood counts may start to drop and patients may develop systemic symptoms, including increased fatigue and night sweats.  If patients receive no treatment, the accelerated phase usually lasts only a matter of months, after which patients enter blast crisis.  Blast crisis resembles AML, with a rapid increase in abnormal myeloblasts and a rapid fall in normal counts.  If untreated, blast crisis CML is usually fatal in a few weeks to months.

Causes

The only clearly identified risk factor for the development of CML is prior radiation exposure.  CML is not hereditary nor is it contagious.

Signs and Symptoms

At the time of diagnosis, most patients are in chronic phase, and as many as 50% of patients are diagnosed incidentally during routine screening or a blood evaluation for an unrelated problem.  Symptoms, when present, may include fatigue, weight loss, bone aches and abdominal discomfort from the development of an enlarged spleen.

Diagnosis of CML

The diagnosis of CML is almost always first suspected because of an increase in the number of granulocytes in the peripheral blood.  Confirmation of the diagnosis requires the demonstration of the BCR/ABL translocation in the leukemic cells.  This is often accomplished by cytogenetic analysis of the bone marrow, but FISH analysis or PCR testing may serve as a substitute.  A bone marrow examination may be useful for documenting the stage of the disease.

Treatment of CML


      Chronic Phase
Therapy of chronic phase CML in the 1980s involved oral busulfan or oral hydroxyurea.  Both are able to reduce abnormal blood count levels and control symptoms for, on average, about 4 years. Thereafter, the disease would progress into accelerated phase or blast crisis, and subsequent survival was measured in months.  In the late 1980’s, interferon alfa was found to be a more effective therapy for CML, extending the average duration of chronic phase to slightly beyond 5 years.  In the late 1990’s, imatinib mesylate was introduced and was compared to interferon in a large randomized trial. In that trial, after six months of therapy only 1% of patients being treated with imatinib had progressive disease compared to 10% of patients treated with interferon. [13] Based on this difference, the study was stopped and imatinib mesylate at a daily dose of 400 mg orally per day became the standard of care. After 5 years, 90% of patients with early chronic phase disease treated with imatinib were alive and 84% progression-free. 
Response to imatinib is determined by monitoring the peripheral blood counts (hematologic response), marrow cytogenetics (cytogenetic response), and PCR measurements of the BCR/ABL fusion product (molecular response).  Hematologic response is the least sensitive test while molecular response is the most sensitive.  The overall duration of response to imatinib appears to be longest in those patients who achieve a complete molecular response, and somewhat shorter in those who achieve a complete cytogenetic response without a complete molecular response. Response durations are considerably shorter in those who fail to achieve a cytogenetic response. It is uncertain if any patients can be cured with imatinib, and in those cases where the drug has been stopped, the disease has quickly reappeared.   
Dasatinib and nilotinib are two newer agents that can induce responses in patients who have failed therapy with imatinib. Clinical trials are now underway comparing imatinib at the conventional dose of 400 mg versus imatinib at higher doses (600 mg or 800 mg), and also comparing imatinib with either dasatinib or nilotinib.  Imatinib can cause nausea, headache, diarrhea, muscle cramps, rash, and peripheral edema, and these toxicities are more common are higher doses.  Both nilotinib and dasatinib can have similar toxicities, but dasatinib is also sometimes associated with the development of a build up of fluid in the lungs (pleural effusions).
Bone marrow transplantation from a matched sibling or matched unrelated donor is able to cure approximately 70% of patients with early phase chronic CML, and was widely used as the initial therapy of choice before the development of imatinib.  Because 10-15% of patients can die as a result of transplant-related toxicities, most patients and physicians prefer to treat with imatinib and only proceed to transplant once imatinib therapy fails.  Although data are limited, it does not appear that prior therapy with imatinib makes transplantation any more risky; however, if transplantation is delayed until patients have progressed to accelerated phase, then outcomes are considerable worse.  Thus, careful monitoring of patients with CML being treated with imatinib is warranted.

      Accelerated Phase and Blast Crisis
Occasionally, patients are already in accelerated phase or blast crisis at the time of diagnosis. Such patients will frequently respond to imatinib, but the responses are less complete and of shorter duration than those seen in chronic phase.  
Patients who progress to accelerated phase or blast crisis while receiving imatinib can sometimes respond briefly to an increase in dose (from 400 to 800 mg/day, for example), but these responses are short lived.  Dasatinib or nilotinib can induce responses in many patients who have failed therapy with imatinib.  Bone marrow transplantation is the only therapy with curative potential in patients with advanced CML.  The procedure has the best chance of working in patients with accelerated phase of blast crisis CML if it is carried out after patients have responded to therapy with dasatinib or nilotinib.

Chronic Lymphocytic Leukemia (CLL) 


Background

CLL is among the most common forms of leukemia, with approximately 10,200 new cases diagnosed in the United States in 2006. The incidence of CLL increases with age and the disease is uncommon in patients less than age 50.

Biology and Classification  

CLL develops when an alteration occurs in a lymphocyte or lymphocyte precursor resulting in its increased proliferation and prolonged survival.  As opposed to AML or ALL, the malignant cells in CLL appear mature and closely resemble normal lymphocytes. The problem is that with time too many malignant lymphocytes accumulate, crowding out normal cells in the marrow and causing enlargement of the liver, spleen and lymph nodes. 
Cases of CLL can be categorized according to the immunophenotype of the leukemic cell, cytogenetics and other molecular markers. Most cases of CLL are of B cell origin, but occasional cases more closely resemble normal T cells.  The leukemic cells in some cases express the surface protein CD38, a finding associated with a more aggressive disease course.  Cytogenetic abnormalities are found in the chromosomes of the majority of CLL cases. Loss of material from chromosome 13 is the most common finding and is associated with slower disease progression, while abnormalities involving 11q or 17p are associated with more rapid disease progression.  A particular gene, ZAP-70, is overexpressed in some cases of CLL, and this finding has been associated with a poorer prognosis. In the course of normal B cell development, the immunoglobulin heavy chain gene is rearranged. In about 50% of cases of CLL, the immunoglobulin heavy chain gene is not be rearranged in the leukemia cell, suggesting that the leukemia arose in a more immature cell. These cases have a somewhat more aggressive disease course than seen in the 50% of CLL cases where the immunoglobulin heavy chain has been rearranged.
CLL is staged using either the Rai or the Binet system.  The Rai system is more commonly used in the United States and is made up of 5 stages, based on the number of cells in the peripheral blood, the involvement of lymph nodes and spleen and residual marrow function (See Table 3). Overall prognosis depends on both the stage of disease, but also the immunophenotypic, cytogenetic and molecular markers noted above.  


Table 3    RAI Classification Staging for CLL 
 
Stage
Feature
Median Survival (years)
0
Lymphocytosis only
 >12
I
Lymphadenopathy
 8.5
II
Splenomegaly
 6
III
Anemia*
 1.5
IV
Thrombocytopenia*
 1.5
* The anemia or thrombocytopenia cannot be immune-mediated


Causes

There are no known environmental risk factors for CLL.  Unlike the other forms of leukemia, neither prior chemotherapy nor radiation exposure appears to increase the incidence of CLL.  There are ethnic differences.  CLL is more common in Ashkenazi Jews of Eastern European ancestry and is much less common in Asian countries.  There is an increased incidence of the disease in families where a prior relative has been diagnosed with the disease.

Signs and Symptoms

In many patients, the diagnosis of CLL is made incidentally when an increased lymphocyte count is noted during a routine examination.  In these asymptomatic patients, there are often no abnormal findings on physical examination, although in about 50% of cases enlargement of the lymph nodes or liver and spleen is found.  In other cases, patients see their physicians because of weakness and fatigue, swollen lymph nodes or spleen, repeated infections, or unintended weight loss. 

Diagnosis of CLL

The diagnosis of CLL requires a sustained increase in mature appearing lymphocytes in the peripheral blood of more than 5000/mm3. Immunophenotyping, cytogenetic, and molecular analysis of the peripheral blood cells helps confirm the diagnosis and provides prognostic information. The finding of an abnormal immunophenotype with a population of B cell markers plus the CD5 antigen helps confirm the diagnosis. Cytogenetic or FISH testing often reveals abnormalities of chromosomes 13, 11, 17 or others. The bone marrow is usually infiltrated with greater than 30% lymphocytes. 

Therapy of CLL

Following the diagnosis of CLL, a first decision is whether to initiate therapy or simply observe the patient.  CLL can take years to progress, and so if patients are asymptomatic, a “watch and wait” approach is sometimes taken.  Often physicians will observe the patient for several months to determine the rate of increase in the peripheral blood lymphocyte count.  If the rate of increase is very slow, than continued watchful waiting is reasonable.  If, however, the peripheral lymphocyte count increases more rapidly, then active therapy may be pursued.  Disease markers, including CD38, ZAP 70, immunoglobulin heavy chain status and cytogenetics are also considered in making the decision to treat or just observe the asymptomatic patient.
A number of different therapies are available for the treatment of CLL.  In the 1980s and 1990s, single agent chlorambucil was the most commonly used treatment.  Randomized trials showed that response rates were higher using fludarabine than chlorambucil. [14]  Subsequently, several trials have found that certain combinations of therapy, such as fludarabine plus cyclophosphamide, or fludarabine plus rituximab, gave higher response rates than fludarabine alone. [15, 16]  Today, in the United States, the most commonly used combinations are fludarabine plus rituximab, or fludarabine plus rituximab plus cyclophosphamide.  These combinations are usually given for four to six cycles.  With such therapy, 35-40% of patients will achieve a complete response and 80-90% will have a partial or complete response.  Following the completion of therapy, patients are generally observed until the disease grows back to a degree requiring further therapy.  The average duration of progression-free survival with modern therapies is in excess of three years, but varies considerably depending on the individual’s disease-specific risk factor. 
The choice of treatment for recurrent CLL depends on a large number of factors.  If the duration of first response was in excess of 18 months, patients will usually respond to retreatment with a fludarabine-containing regimen, similar to that used for initial therapy.  If the duration of first remission was short, alternative therapies are usually considered.  Alemtuzumab, an antibody against the CD52 antigen, is approved for the treatment of recurrent CLL. 
Patients with less aggressive CLL can live for many years with their disease.  However, with time, the disease can become less sensitive to available therapies.  Progressive CLL may cause anemia by crowding out normal red cell production, resulting in a need for red cell transfusions.  In other cases, the abnormal lymphocytes can destroy normal red cells resulting in a hemolytic anemia that requires therapy with prednisone or a similar steroid. Recurrent infections can become a problem because of drops in normal immunoglobulin producing cells.  Thus, some patients may benefit from infusions of immunoglobulin. Splenic enlargement may cause pain in the left-upper quadrant requiring splenectomy.  In some cases, the abnormal lymphocytes may change in their characteristics and begin to grow rapidly as masses in the lymph nodes, similar to a lymphoma.  This change is called “Richter’s transformation” and usually is treated using chemotherapeutic agents similar to those used to treat non-Hodgkin lymphoma.
Although current standard chemotherapies can extend the life of patients with CLL for many years, none are able to cure the disease. The only curative therapy is allogeneic hematopoietic cell transplantation. Because of the toxicities of transplantation, its use is usually reserved for younger, healthier patients with high risk disease who have failed first line conventional therapy.  With the development of reduced intensity transplant regimens, this approach is now being tested in patients in the 60s and 70s.     

Reference List

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3.          Levi I, Grotto I, Yerushalmi R, Ben-Bassat I, Shpilberg O. Meta-analysis of autologous bone marrow transplantation versus chemotherapy in adult patients with acute myeloid leukemia in first remission. Leuk Res 2004; 28:605-612.
4.          Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, Paietta E, Willman CL, Head DR, Rowe JM, Forman SJ, Appelbaum FR: Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study. Blood 2000;96:4075-4083.
5.          Schlenk RF, Corbacioglu A, Krauter J, Bullinger L, Morgan M, Spath D, Schafer I, Frohling S, Ganser A, Dohner H, Dohner K. Gene mutations as predictive markers for postremission therapy in younger adults with normal karyotype AML. Blood (ASH Annual Meeting Abstracts) 2006; 108:6a.
6.          Appelbaum FR, Gundacker H, Head DR, Slovak ML, Willman CL, Godwin JE, Anderson JE, Petersdorf SH: Age and acute myeloid leukemia. Blood 2006;107:3481-3485.
7.          Burnett AK, Milligan D, Prentice AG, Goldstone AH, McMullin MF, Hills RK, Wheatley K. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 2007;109:1114-24.
8.          Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Woods WG, Ogden A, Weinstein H, Shepherd L, Willman C, Bloomfied CD, Rowe JM, Wiernik PH: All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 2002;100:4298-4302.
9.          Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, Stone RM, Kalaycio M, Scheinberg DA, Steinherz P, Sievers EL, Coutré S, Dahlberg S, Ellison R, Warrell RP, Jr.: United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001;19:3852-3860.
10.       Yanada M, Takeuchi J, Sugiura I, Akiyama H, Usui N, Yagasaki F, Kobayashi T, Ueda Y, Takeuchi M, Miyawaki S, Maruta A, Emi N, Miyazaki Y, Ohtake S, Jinnai I, Matsuo K, Naoe T, Ohno R: High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol 2006;24:460-466.
11.       Thomas DA, Faderl S, O’Brien S, Bueso-Ramos C, Cortes J, Garcia-Manero G, Giles F, Verstovsek S, Wierda W, Pierce S, Shan J, Brandt M, Hagemeister F, Cabanillas F, Keating MJ, Kantarjian H. Chemo-Immunotherapy with Hyper-CVAD Plus Ritixumab for Adult Burkitt's and Burkitt's Type Lymphoma (BL) or Acute Lymphoblastic Leukemia (B-ALL). Blood ASH Annual Meeting Abstracts 2005 106: 47a.
12.       Balduzzi A, Valsecchi M, Uderzo C, De Lorenzo P, Klingebiel T, Peters C, Stary J, Felice MS, Magyarosy E, Conter V, Reiter A, Messina C, Gadner H, Schrappe M. Chemotherapy versus allogeneic transplantation for very high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study.  Lancet 2005; 366:635-642.
13.       O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ, I.R.I.S.Investigators: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994-1004.
14.       Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Sheperd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA: Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 2000;343:1750-1757.
15.       Eichhorst BE, Bush R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, Siehl S, Jäger U, Bergmann M, Stilgenbauer S, Schweighofer C, Wendtner CM, Döhner H, Brittinger G, Emmerich B, Hallek M; German CLL Study Group. Fludarabine plus cyclophosphamide versus fludarabine alone in younger patients with chronic lymphocytic leukemia. Blood 2006;107: 885-889.
16.       Byrd JC, Rai K, Peterson BL, Appelbaum FR, Morrison VA, Kolitz JE, Shepherd L, Hines JD, Schiffer CA, Larson RA: Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALBG 9712 and CALBG 9011. Blood 2005;105:49-53.