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I. Background:
Acute lymphoblastic leukemia (ALL) is a malignant (clonal) disease of the bone marrow in
which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the
marrow. ALL may be distinguished from other malignant lymphoid disorders by the
immunophenotype of the cells, which is similar to B- or T-precursor cells. Immunochemistry,
cytochemistry, and cytogenetic markers also may aid in categorizing the malignant lymphoid
clone.
II. Epidemiology :
ALL is the most common type of leukemia in children. In adults, it is less common than acute
myelogenous leukemia (AML). In the United States, approximately 1.000 new cases of ALL
occur in adults each year. Only 20-40% of adults with ALL are cured with current regimens.
ALL is slightly more common in men than in women and it is more common in children than in
adults.
III. Etiology :
Less is known about the etiology of ALL in adults compared with AML. Most adults
with ALL have no identifiable risk factors.
An increased prevalence of ALL was noted in survivors of the Hiroshima atomic bomb
but not in those who survived the Nagasaki atomic bomb. Most leukemias occurring after
exposure to radiation are AML rather than ALL.
As many as 10-15% of adults and 2-5% of children have a positive finding for the
Philadelphia chromosome, suggesting a preexisting myeloproliferative disorder, ie,
chronic myelocytic leukemia. Most cases of myeloproliferative disorders that progress to
acute leukemia progress to AML rather than ALL.
IV. Pathophysiology:
The malignant cells of ALL are lymphoid precursor cells (ie, lymphoblasts) that are arrested in
an early stage of development. This arrest is caused by an abnormal expression of genes, often as
a result of chromosomal translocations. The lymphoblasts replace the normal marrow elements,
resulting in a marked decrease in the production of normal blood cells. Consequently, anemia,
thrombocytopenia, and neutropenia occur to varying degrees. The lymphoblasts also proliferate
in organs other than the marrow, particularly the liver, spleen, and lymph nodes.
V. Clinic
V.1. History:
Patients with ALL present with either (1) symptoms relating to direct infiltration of the marrow
or other organs by leukemic cells or (2) symptoms relating to the decreased production of normal
marrow elements.
1. symptoms relating to direct infiltration of the marrow or other organs by leukemic cells :
bone pain due to infiltration of the marrow by massive numbers of leukemic cells. This
pain can be severe and is often atypical in distribution.
left upper quadrant fullness and early satiety due to splenomegaly (10-20%),
symptoms related to a large mediastinal mass, such as shortness of breath, particularly
those with T-cell ALL, present with.
patients may present with symptoms of leukostasis (eg, respiratory distress, altered
mental status) because of the presence of large numbers of lymphoblasts in the peripheral
circulation
2. symptoms relating to the decreased production of normal marrow elements :
symptoms of anemia are common and include fatigue, dizziness, palpitations, and
dyspnea upon even mild exertion.
patients with ALL often have decreased neutrophil counts, despite an increased total
WBC count. As a result, they are at increased risk of infection. Infections are common
when the absolute neutrophil count is less than 500/L and are especially severe when it
is less than 100/L.
patients with ALL often have fever without any other evidence of infection. However, in
these patients, one must assume that all fevers are from infections until proven otherwise
because a failure to treat infections promptly and aggressively can be fatal. Infections are
still the most common cause of death in patients undergoing treatment for ALL.
some patients may present with hemorrhagic or thrombotic complications. Bleeding
symptoms are usually more often the result of a coexisting thrombocytopenia caused by
marrow replacement Approximately 10% of patients with ALL have disseminated
intravascular coagulation (DIC) at the time of diagnosis, usually as a result of sepsis.
V.2. Physical:
Patients commonly have physical signs of anemia, including pallor and a cardiac flow
murmur (anemic syndrome).
Fever and other signs of infection, including lung findings of pneumonia, can occur.
Fever should be interpreted as evidence of infection, even in the absence of other signs
(infectious syndrome).
Patients with thrombocytopenia usually demonstrate petechiae, particularly on the lower
extremities. A large number of ecchymoses is usually an indicator of a coexistent
coagulation disorder such as DIC (hemorrhagic syndrome).
Signs relating to organ infiltration with leukemic cells include hepatosplenomegaly and,
to a lesser degree, lymphadenopathy (tumoral syndrome).
Occasionally, patients have rashes resulting from infiltration of the skin with leukemic
cells.
VI. Investigations :
VI.1. Lab Studies:
A CBC count with differential demonstrates anemia and thrombocytopenia to varying degrees.
The WBC count may be high(leukocytosis), normal, or low, but usually exhibit neutropenia and
the presence of blast cells without intermediary cells (leukemic gap).
A review of the peripheral blood smear confirms the findings of the CBC count.
Circulating blasts are usually seen. Schistocytes are sometimes seen if DIC is present.
Abnormalities in the prothrombin time/activated partial thromboplastin
time/fibrinogen/fibrin degradation products may suggest concomitant DIC, which results in an
elevated prothrombin time, decreased fibrinogen levels, and the presence of fibrin split products.
A chemistry profile is recommended. It shows in most patients an elevated lactic
dehydrogenase (LDH) level and frequently an elevated uric acid level. Liver function tests and
BUN/creatinine determinations are necessary prior to the initiation of therapy.
Appropriate cultures, in particular blood cultures, should be obtained in patients with
fever or with other signs of infection without fever. A viral study for HIV, HTLV, CMV, EBV,
Hepatitis B and C is needed.
VI.3. Procedures:
Bone marrow aspiration and biopsy are the definitive diagnostic tests to confirm the diagnosis of
leukemia, although immunophenotyping helps elucidate the subtype.
Aspiration slides should be stained for morphology with either Wright or Giemsa stain. In
addition, slides should be stained with myeloperoxidase (or Sudan black), and periodic acid
Schiff (PAS). The diagnostic and subtyping is completed by immunophenotyping (flow
cytometry and immunohistochemistry) and cytogenetics.
the morphologic exam shows the lymphoblastic features (see FAB Classification below)
a negative myeloperoxidase stain is the hallmark for the diagnosis of most cases of ALL.
a positive confirmation of lymphoid (and not myeloid) lineage should be sought by flow
cytometric demonstration of lymphoid antigens, such as CD3 (T-lineage ALL) or CD19
(B-lineage ALL), in order to avoid confusion with the rare types of myeloid leukemia
(eg, M0, acute monocytic leukemia), which also stain negative with myeloperoxidase
(table 3).
Studies for bcr-abl analysis by polymerase chain reaction or cytogenetics may help
identify those patients in whom ALL arose as the lymphoblastic phase of chronic
myelogenous leukemia.
cytogenetic exam may help identify cytogenetic abnormalities with prognostic
significance (table 1 and 2)
Bone marrow samples should also be sent for cytogenetics and flow cytometry.
Approximately 15% of patients with ALL have a t(22;9) translocation (ie, Philadelphia
chromosome), but other chromosomal abnormalities also may occur, such as t(4;11), t(2;8), and
t(8;14)
Table 3. Immunophenotyping of ALL Cells - ALL of B-Cell Lineage (80% of cases of adult
ALL)
ALL Cells TdT CD19 CD10 CyIg* SIg
Early B-precursor ALL + + - - -
PreB-cell ALL + + + + -
B-cell ALL - + +/- +/- +
*Cytoplasmic immunoglobulin
Surface immunoglobulin
Table 4. Immunophenotyping of ALL Cells - ALL of T-Cell Lineage (20% of cases of adult
ALL)
ALL Cells TdT CD7 CD2
Early T-precursor ALL + + -
T-cell ALL + + +
VII. Prognosis:
Patients with ALL are divided into 3 prognostic groups.
Good risk includes (1) no adverse cytogenetics, (2) age younger than 30 years, (3) WBC
count of less than 30,000/L, and (4) complete remission within 4 weeks.
Intermediate risk does not meet the criteria for either good risk or poor risk.
Poor risk includes (1) adverse cytogenetics [(t9;22), (4;11)], (2) age older than 60 years,
(3) precursor B-cell WBCs with WBC count greater than 100,000/L, or (4) failure to
achieve complete remission within 4 weeks.
The effect of chromosome number on prognosis is displayed in Table 2.
VIII. Medical Care :
Currently, only 20-30% of adults with ALL are cured with standard chemotherapy regimens.
Consequently, all patients must be evaluated for entry into well-designed clinical trials. If a
clinical trial is not available, the patient can be treated with standard therapy. Traditionally, the 4
components of ALL treatment are induction, consolidation, maintenance, and CNS prophylaxis.
VIII.6. Transplantation
Allogeneic transplantation is effective therapy for :
high-risk patients were considered (ie, Ph+, null ALL, >35 y, WBC count
>30,000/L, or time to complete remission >4 wk),
patients who have experienced relapse after chemotherapy.
most authorities agree that :
allogeneic transplantation should be offered to young patients with high-risk
features whose disease is in first remission.
young patients without adverse features should receive induction, consolidation,
and maintenance therapy. In these patients, transplantation is reserved for relapse.
older patients whose disease is in complete remission may be considered for such
investigational approaches as allogeneic transplantation with nonmyeloablative
chemotherapy (ie, minitransplants).
Although previously patients with mature B-cell ALL would have been referred for
transplantation when their disease was in first complete remission, with improving results
from more intensive chemotherapy regimens, many are reserving transplantation for
patients who have experienced relapse.
For patients without a sibling donor, an alternative is an unrelated donor (URD)
transplant.
.
VIII.7. Treatment of relapsed ALL
Patients with relapsed ALL have an extremely poor prognosis. Most patients are referred for
investigational therapies. Young patients who have not previously undergone transplantation are
referred for such therapy. Reinduction regimens include the hyper-CVAD protocol and high-
dose Ara-Cbased regimens.
The hyper-CVAD regimen is based on hyperfractionated cyclophosphamide and
intermediate doses of Ara-C and methotrexate. With this regimen the complete remission rate
was 44% and median survival was 42 weeks.
Allopurinol at 300 mg 1-3 times/d is recommended during induction therapy until blasts
are cleared and hyperuricemia resolves.
XI. Complications:
Death may occur as a result of uncontrolled infection or hemorrhage. This may occur even after
the use of appropriate blood product and antibiotic support.
The most common complication is failure of the leukemia to respond to chemotherapy.
These patients do poorly because they usually do not respond to other chemotherapy regimens.