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/mm3. Occasionally 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.
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