ACUTE LLYMPHOBLASTIC LEUKEMIA
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.2. Imaging Studies:
 Chest x-ray films may reveal signs of pneumonia and/or a prominent mediastinal mass in
some cases of T-cell ALL.
 An ECG is needed when the diagnosis is confirmed because many chemotherapeutic
agents used in the treatment of acute leukemia are cardiotoxic.
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)
VI.4. Histologic Findings:
French-American-British Classification
 L1 - Small cells with homogeneous chromatin, regular nuclear shape, small or absent
nucleolus, and scanty cytoplasm; subtype represents 25-30% of adult cases
 L2 - Large and heterogeneous cells, heterogeneous chromatin, irregular nuclear shape,

and nucleolus often large; subtype represents 70% of cases (most common)
L3 - Large and homogeneous cells and cytoplasmic vacuolization that often overlies the
nucleus (most prominent feature); subtype represents 1-2% of adult cases.
Table 1. Common Cytogenetic Abnormalities in ALL
Abnormality
Genes Involved Three-Year, Event-Free Survival
t(10;14)(q24;q11) HOX11/TCRA
75%
6q
Unknown
47%
14q11
TCRA/TCRD
42%
11q23
MLL
18-26%
9p
Unknown
22%
12
TEL
20%
t(1;19)(q23;p13)
PBX1/E2A
20%
t(8;14)(q24;q23)
t(2;8)(p12;q24)
t(8;22)(q24;q11)
c-myc/IGH
IGK/c-myc
c-myc/IGL
17%
t(9;22)(q34;q11)
bcr-abl
5-10%
t(4;11)(q21;q23)
AF4-MLL
0-10%
Table 2. Effect of Chromosome Number on Prognosis
Chromosome Number
Three-Year, Event-Free Survival
Near tetraploidy
46-56%
Normal karyotype
34-44%
Hyperdiploidy >50
32-59%
Hyperdiploidy 47-50
21-53%
Pseudodiploidy
12-25%
Hypodiploidy
11%
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
+
+
-
-
-
Pre–B-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.1. Induction therapy
 The goal of induction therapy is to achieve complete remission(CR) that is, eradication of
leukemia as determined by morphological criteria (a normal CBC count with < 1% blast
cells in the bone marrow) and recently also by molecular markers;
 Standard induction therapy typically involves either a 4-drug regimen of vincristine,
prednisone, anthracycline (Daunorubicine, Idarubicine), and cyclophosphamide or Lasparaginase or a 5-drug regimen of vincristine, prednisone, anthracycline,
cyclophosphamide, and L-asparaginase given over the course of 4-6 weeks.
 Using this approach, complete remissions are obtained in 65-85% of patients. The
rapidity with which a patient's disease enters complete remission is correlated with
treatment outcome.
 The response to the treatment is evaluated when the patient recuperate after posttherapeutical aplasia.
 Patients in complete remission within 4 weeks of therapy have longer disease-free
survival and overall survival than those whose disease enters remission after 4 weeks of
treatment.
 A more recent strategy to improve the therapy is to add high-dose cytosine arabinoside
(HdAC).
VIII.2. Consolidation therapy
 The aim of this treatment is to eliminate clinically undetectable residual leukemia after
induction therapy and thereby to prevent relapse as well as the emergence of drug
resistand cells.
 Because most studies showed a benefit to consolidation therapy, regimens using a
standard 4- to 5-drug induction usually include consolidation therapy with Ara-C in
combination with an anthracycline or epipodophyllotoxin.
VIII.3. Maintenance therapy
 The aim of maintenance therapy is to eliminate minimal residual disease diminishing the
risk of relapse and increasing survival.
 The effectiveness of maintenance chemotherapy in adults with ALL has not been studied
in a controlled clinical trial so the optimal and form of maintenance in adult ALL is
unknown.
 Standard maintenance therapy is based on combination treatment with 6-mercaptopurine
(6-MP) given daily and methotrexate given weekly for 24-36 months.
 There is a need for prospective trials with maintenance schedules adapted to
immunological subtypes.
VIII.4. CNS prophylaxis
 In contrast to patients with AML, patients with ALL frequently have meningeal leukemia
at the time of relapse. A minority of patients have meningeal disease at the time of initial
diagnosis. As a result, CNS prophylaxis with intrathecal chemotherapy is essential.
 Different studies demonstrated that high-dose systemic chemotherapy reduces CNS
relapse; however, early intrathecal chemotherapy is necessary to achieve the lowest risk
of CNS relapse.
 Good result were achieved with high-dose systemic chemotherapy associated with
intrathecal therapy with methotrexar as single drug, four times in induction phase and
four times in consolidation phase, and central nervous system irradiation with 24 Gy.
 Prophylactic treatment of the CNS may result in acute or chronic neurotoxicity
VIII.5. Newer approaches
 Standard induction regimens were originally developed when supportive care was
significantly inferior to what is available today. Few antibiotics were available, and
transfusion capabilities were minimal. Consequently, milder regimens were designed in
an attempt to minimize early deaths during induction.
 With the addition of third-generation cephalosporins and sophisticated blood-banking
techniques, the ability to support patients through a pancytopenic phase has increased
dramatically. As a result, the use of more intensive induction approaches is being studied
with higher doses of cytostatic drugs
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 highdose Ara-C–based 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.
VIII.8. Supportive care with replacement of blood products
Patients have a deficiency in the ability to produce normal blood cells, and they need
replacement therapy. This deficiency is temporarily worsened by the addition of chemotherapy.
 All blood products must be irradiated to prevent transfusion-related graft versus host
disease, which is almost invariably fatal.
 Packed red blood cells are given to patients with a hemoglobin level of less than 7-8 g/dL
or at a higher level if the patient has significant cardiovascular or respiratory
compromise.
 Platelets are transfused if the count is less than 10,000-20,000/L. Patients with
pulmonary or gastrointestinal hemorrhage receive platelet transfusions to maintain a
value greater than 50,000/L. Patients with CNS hemorrhage are transfused to achieve a
platelet count of 100,000/L.
 Fresh frozen plasma is given to patients with a significantly prolonged prothrombin time,
and cryoprecipitate is given if the fibrinogen level is less than 100 g/dL.
VIII.9. Supportive care with antibiotics
These are given to all febrile patients. At a minimum, include a third-generation cephalosporin
(or equivalent), usually with an aminoglycoside. In addition to this minimum, other antibiotics
are added to treat specific documented or possible infections.
Patients with persistent fever after 3-5 days of antibacterial antibiotics have amphotericin
added to their regimen.
 Patients with a fever without a focus of infection receive amphotericin at a dose of 0.5
mg/kg.
 Patients with sinopulmonary symptoms receive 1 mg/kg.
 Particular care is warranted for patients receiving steroids as part of their treatment
because the signs and symptoms of infection may be subtle or even absent.
The use of prophylactic antibiotics in neutropenic patients who are not febrile is
controversial. However, most clinicians prescribe them for patients undergoing induction
therapy. A commonly used regimen includes ciprofloxacin (500 mg orally twice daily,
fluconazole (Diflucan) (200 mg orally daily), and acyclovir (200 mg orally 5 times/d).
Once patients taking these antibiotics become febrile, they are switched to intravenous
antibiotics per above.
VIII.10. Supportive care with growth factors
The use of granulocyte colony-stimulating factor (G-CSF) during induction reduced the
prevalence of febrile neutropenia and decreased the prevalence of documented infections.
Subjects with G-CSF had significantly shorter durations of neutropenia and significantly fewer
days of hospitalization. They also had higher complete remission rates because fewer deaths
occurred during remission induction, but no difference was observed in response, remission
duration, or survival between the 2 groups (with or without growth factor).
Allopurinol at 300 mg 1-3 times/d is recommended during induction therapy until blasts
are cleared and hyperuricemia resolves.
Diet: A neutropenic diet is recommended.
 No fresh fruits or vegetables may be eaten.
 All foods must be cooked.
 Meats are to be cooked until well done.
IX. Further Inpatient Care:
Patients require admission for induction chemotherapy and require readmission for consolidation
chemotherapy or for the treatment of toxic effects of chemotherapy.
Patients are best treated at a center with personnel who have significant experience in the
treatment of leukemia. Patients admitted to hospitals that lack appropriate blood product support
facilities, leukapheresis capabilities, or physicians and nurses familiar with the treatment of
patients with leukemia should be transferred to an appropriate (generally tertiary care) hospital.
X. Further Outpatient Care:
Maintenance therapy is administered in an outpatient setting. Patients come to the office to be
monitored for disease status and the effects of chemotherapy.
While talking chemotherapy, patients with leukemia should avoid exposure to crowds
and people with contagious illnesses, especially children with viral infections.
Patients should be instructed to immediately seek medical attention if they are febrile or
have signs of bleeding.
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.