Practice EssentialsAcute 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 is the most common type of
cancer and leukemia in children in the United States. The image
below shows preB-cell ALL.Diagnostic workup of a patient with
preB-cell acute lymphoblastic leukemia. Bone marrow aspiration
revealed French-American-British L2 morphology. Essential update:
FDA approves first of new class of drugs for relapsed or refractory
B-cellderived ALLThe FDA has approved blinatumomab (Blincyto) for
the treatment of patients with Philadelphia chromosomenegative
precursor B-cell ALL that has relapsed or is refractory to other
treatment. Blinatumomab is the first of a novel class of drugs
known as bispecific T-cell engagers; it is designed to promote
cancer cell lysis by simultaneously binding with CD3 on cytotoxic
T-cells and with CD19, which is expressed on the surface of
B-cellderived ALL (and also non-Hodgkin lymphomas).[1, 2] Approval
was based on a study of 185 adult patients in which 32% experienced
complete remission for approximately 6.7 months after at least 4
weeks of infusion treatment. Labeling includes a boxed warning on a
risk of low blood pressure and difficulty breathing as a result of
cytokine-release syndrome when treatment is initiated. Cases of
encephalopathy and other central nervous system adverse events were
also observed in the pre-approval study. A postmarketing study will
be conducted to verify that blinatumomab improves survival.[1, 2]
Signs and symptomsSigns and symptoms of ALL include the following:
Fever Decreased neutrophil count Signs and symptoms of anemia, such
as pallor, fatigue, dizziness, palpitations, cardiac flow murmur,
and dyspnea with even mild exertion Bleeding (eg, from
thrombocytopenia due to marrow replacement) Disseminated
intravascular coagulation (DIC) at diagnosis (about 10% of cases)
Palpable lymphadenopathy Symptoms related to a large mediastinal
mass (eg, shortness of breath), particularly with T-cell ALL Bone
pain (severe and often atypical) Left upper quadrant fullness and
early satiety due to splenomegaly (about 10-20% of cases) Symptoms
of leukostasis (eg, respiratory distress, altered mental status)
Renal failure in patients with a high tumor burden Infections,
including pneumonia Petechiae (particularly on lower extremities)
and ecchymoses Signs relating to organ infiltration with leukemic
cells and lymphadenopathy Rashes from skin infiltration with
leukemic cellsSee Clinical Presentation for more
detail.DiagnosisLaboratory tests and other studies used in the
workup for ALL include the following: Complete blood count with
differential Coagulation studies Peripheral blood smear Chemistry
profile, including lactic dehydrogenase, uric acid, liver function
studies, and BUN/creatinine Appropriate cultures (in particular,
blood cultures) in patients with fever or other signs of infection
Chest x-ray Computed tomography Multiple-gated acquisition scanning
Electrocardiography Bone marrow aspiration and biopsy (definitive
for confirming leukemia) Immunohistochemistry Flow cytometry
Cytogenetics Polymerase chain reaction Gene expression profilingSee
Workup for more detail.ManagementTreatment of ALL may include the
following: Induction chemotherapy (eg, standard 4- or 5-drug
regimen, ALL-2, or hyper-CVAD) Consolidation chemotherapy
Maintenance chemotherapy Intrathecal chemotherapy for central
nervous system (CNS) prophylaxis Supportive care (eg, blood
products, antibiotics, growth factors)Special considerations apply
to the treatment of the following: Mature B-cell ALL Ph+ ALL ALL in
older children and younger adults Relapsed ALL ALL in patients with
hyperuricemia or at high risk for tumor lysis syndromeSee Treatment
and Medication for more detail.BackgroundAcute 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 may also
aid in categorizing the malignant lymphoid clone. The image below
shows preB-cell ALL.Diagnostic workup of a patient with preB-cell
acute lymphoblastic leukemia. Bone marrow aspiration revealed
French-American-British L2 morphology. See also Pediatric Acute
Lymphoblastic Leukemia and Acute Myelogenous
Leukemia.PathophysiologyThe malignant cells of acute lymphoblastic
leukemia (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.Etiology Less is known about the
etiology of acute lymphoblastic leukemia (ALL) in adults compared
with acute myelogenous leukemia (AML). Most adults with ALL have no
identifiable risk factors. Although most leukemias occurring after
exposure to radiation are AML rather than ALL, an increased
prevalence of ALL was noted in survivors of the Hiroshima atomic
bomb but not in those who survived the Nagasaki atomic bomb. Rare
patients have an antecedent hematologic disorder (AHD) such as
myelodysplastic syndrome (MDS) that evolves to ALL. However, most
patients with MDS that evolves to acute leukemia develop AML rather
than ALL.Increasingly, cases of ALL with abnormalities of
chromosome band 11q23 following treatment with topoisomerase II
inhibitors for another malignancy have been described. However,
most patients who develop secondary acute leukemia after
chemotherapy for another cancer develop AML rather than ALL.
EpidemiologyAcute lymphoblastic leukemia (ALL) is the most common
type of cancer and leukemia in children in the United States. ALL
accounts for 26% of all cancers in children up to 14 years of age,
and for 75% of pediatric leukemia cases.[3] In adults, this disease
is less common than acute myelogenous leukemia (AML). Approximately
1000 new cases of ALL occur in adults each year. However, due to
the fact that there are more adults than children, the number of
cases seen in adults is comparable to that seen in children. ALL is
slightly more common in males than in females. Worldwide, the
highest incidence of ALL occurs in Italy, the United States,
Switzerland, and Costa Rica.Prognosis Only 20-40% of adults with
acute lymphoblastic leukemia (ALL) are cured with current treatment
regimens.Patients with ALL are divided into three prognostic
groups: good risk, intermediate risk, and poor risk.Good risk
criteria include the following: No adverse cytogenetics Age younger
than 30 years White blood cell (WBC) count of less than 30,000/L
Complete remission within 4 weeksIntermediate risk includes those
whose condition does not meet the criteria for either good risk or
poor risk.Poor risk criteria include the following: Adverse
cytogenetics Translocations t(9;22), t(4;11) Age older than 60
years Precursor B-cell WBCs with WBC count greater than 100,000/L
Failure to achieve complete remission within 4 weeksPatients with
precursor B-cell ALL have an extremely poor prognosis. Essentially,
following standard chemotherapy or autologous transplantation,
long-term survival is not achieved. Several reports have indicated
that some patients with precursor B-cell ALL and t(4;11) may have
prolonged survival following allogeneic transplantation; therefore,
this is the treatment of choice. Immunophenotype effects on
prognosisCzuczman et al studied 259 patients treated with several
Cancer and Leukemia Group B (CALGB) protocols for newly diagnosed
ALL and found no significant difference in response rates,
remission duration, or survival for patients expressing myeloid
antigens versus those not expressing myeloid antigens.[4] B-lineage
phenotype was expressed in 79% of patients; one third of these
coexpressed myeloid antigens. Seventeen percent of patients
demonstrated T-lineage ALL; one quarter of these coexpressed
myeloid antigens.[4] T-lineage ALL was associated with younger age,
male sex, presence of a mediastinal mass, higher WBC count and
hemoglobin level, longer survival, and longer disease-free
survival. The number of T markers expressed also had prognostic
significance. Patients expressing six or more markers had longer
disease-free and overall survival compared with patients expressing
three or fewer markers. In a report by Preti et al, 64 of 162
patients with newly diagnosed ALL coexpressed myeloid markers.[5]
Patients coexpressing myeloid markers were significantly older, had
a higher prevalence of CD34 expression, and had a lower prevalence
of common ALL antigen expression than patients without myeloid
expression. A trend toward a decreased remission rate was observed
for patients coexpressing myeloid markers (64%) relative to those
who did not coexpress such markers (78%).[5] However, no
significant effect on remission duration or overall survival was
observed. Chromosome number and prognosisThe effect of chromosome
number on prognosis is displayed in Table 1, below.Table 1. Effect
of Chromosome Number on Prognosis (Open Table in a new
window)Chromosome Number3-Year Event-Free Survival
Near tetraploidy46-56%
Normal karyotype34-44%
Hyperdiploidy >5032-59%
Hyperdiploidy 47-5021-53%
Pseudodiploidy12-25%
Hypodiploidy11%
Complications and prognosisA study by Ness et al found
neuromuscular impairments were prevalent in survivors of childhood
ALL and these impairments interfered with physical performance.[6]
Increased cumulative doses of intrathecal methotrexate and/or
vincristine were associated with long-term neuromuscular
impairments, and these have implications on future function with
age.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.Death in
those with ALL may occur as a result of uncontrolled infection or
hemorrhage. This may occur even after the use of appropriate blood
product and antibiotic support. Patient Education Patients with
acute lymphoblastic leukemia (ALL) should be instructed to
immediately seek medical attention if they are febrile or have
signs of bleeding. Furthermore, while receiving chemotherapy,
patients with leukemia should avoid exposure to crowds and people
with contagious illnesses, especially children with viral
infections. Although activity may occur as tolerated, patients with
ALL may not participate in strenuous activities such as lifting or
exercise. In addition, a neutropenic diet is recommended in these
individuals, as follows: No fresh fruits or vegetables may be eaten
All foods must be cooked Meats are to be cooked until well doneFor
patient education information, see Blood and Lymphatic System
Center and Cancer and Tumors Center, as well as
Leukemia.HistoryPatients with acute lymphoblastic leukemia (ALL)
present with either symptoms relating to direct infiltration of the
marrow or other organs by leukemic cells, or symptoms relating to
the decreased production of normal marrow elements. Fever is one of
the most common symptoms of ALL, and 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
proved 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. Patients
with ALL often have decreased neutrophil counts, regardless of
whether their total white blood cell (WBC) count is low, normal, or
elevated. As a result, these individuals are at an increased risk
of infection. The prevalence and severity of infections are
inversely correlated with the absolute neutrophil count (ANC),
which is defined as the number of mature neutrophils plus bands per
unit of volume. Infections are common when the absolute neutrophil
count is less than 500/L, and they are especially severe when it is
less than 100/L. See the Absolute Neutrophil Count calculator.
Symptoms of anemia are common and include fatigue, dizziness,
palpitations, and dyspnea upon even mild exertion. Other patients
present with signs of bleeding. Bleeding can be the result of
thrombocytopenia due to marrow replacement. Additionally,
approximately 10% of patients with ALL have disseminated
intravascular coagulation (DIC) at the time of diagnosis. These
patients may present with hemorrhagic or thrombotic complications.
Some patients present with palpable lymphadenopathy. Others,
particularly those with T-cell ALL, present with symptoms related
to a large mediastinal mass, such as shortness of breath.
Infiltration of the marrow by massive numbers of leukemic cells
frequently manifests as bone pain. This pain can be severe and is
often atypical in distribution. About 10-20% of ALL patients may
present with left upper quadrant fullness and early satiety due to
splenomegaly.Although 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, leukostasis is much less common in people
with ALL than those with acute myelogenous leukemia (AML), and it
occurs only in patients with the highest WBC counts (ie, several
hundred thousand per L). Patients with a high tumor burden,
particularly those with severe hyperuricemia, can present in renal
failure.Physical ExaminationPatients with acute lymphoblastic
leukemia (ALL) commonly have physical signs of anemia, including
pallor and a cardiac flow murmur. Fever and other signs of
infection, including lung findings of pneumonia, can also occur.
Fever should be interpreted as evidence of infection, even in the
absence of other signs. 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 disseminated intravascular coagulation
(DIC). Signs relating to organ infiltration with leukemic cells
and, to a lesser degree, lymphadenopathy may be
present.Occasionally, patients have rashes that result from
infiltration of the skin with leukemic cells.Other conditions that
should be considered in the evaluation of suspected acute ALL
include acute biphenotypic leukemia and natural killer (NK)-cell
leukemia. Differential Diagnoses Acute Myelogenous Leukemia
Lymphoma, B-Cell Lymphoma, High-Grade Malignant Immunoblastic
Lymphoma, Mantle Cell Lymphoma, Non-HodgkinApproach
ConsiderationsThe following studies and procedures are used in the
workup for acute lymphoblastic leukemia (ALL): Complete blood count
(CBC) with peripheral smear Coagulation studies Chemistry profile,
including liver and renal function studies Bone marrow aspiration
and biopsy Definitive diagnostic tests Cultures, in particular
blood cultures Chest radiography Chest computed tomography (CT)
scan Multiple-gated acquisition (MUGA) scan or electrocardiogram
(ECG)National Comprehensive Cancer Network (NCCN) guidelines note
that diagnosis of ALL generally requires the following[7] :
Demonstration of 20% bone marrow lymphoblasts Morphologic
assessment of Wright/Giemsastained bone marrow aspirate smears
Hematoxylin and eosin (H&E)stained bone marrow core biopsy and
clot sections Comprehensive flow cytometric immunophenotypingFor
optimal risk stratification and treatment planning in patients with
ALL, the NCCN advises that bone marrow or peripheral blood
lymphoblasts must be tested for specific recurrent genetic
abnormalities, as follows[7] : Cytogenetics Karyotyping of G-banded
metaphase chromosomes Interphase fluorescence in situ hybridization
(FISH) Reverse transcriptase polymerase chain reaction (RT-PCR) for
fusion genes (eg, BCR-ABL)In addition, flow cytometric DNA
index/ploidy testing can be done to assess for hyperdiploidy and
hypodiploidy.See also Acute Lymphoblastic Leukemia Staging.Routine
Laboratory StudiesA complete blood cell (CBC) count with
differential demonstrates anemia and thrombocytopenia to varying
degrees in individuals with acute lymphoblastic leukemia (ALL).
Patients with ALL can have a high, normal, or low white blood cell
(WBC) count, but they usually exhibit neutropenia. The prevalence
and severity of infections are inversely correlated with the
absolute neutrophil count (ANC); infections are common when the
absolute neutrophil count is less than 500/L, and they are
especially severe when it is less than 100/L. See the Absolute
Neutrophil Count calculator. Coagulation studies and chemistry
profilesAbnormalities in the prothrombin time (PT) / activated
partial thromboplastin time (aPTT) / fibrinogen / fibrin
degradation products may suggest concomitant disseminated
intravascular coagulation (DIC), which results in an elevated PT,
decreased fibrinogen levels, and the presence of fibrin split
products. 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. A chemistry
profile is recommended. Most patients with ALL have an elevated
lactic dehydrogenase level (LDH), and they frequently have an
elevated uric acid level. In addition, liver function tests and
blood urea nitrogen (BUN)/creatinine determinations are necessary
before the initiation of therapy. CulturesAppropriate cultures, in
particular blood cultures, should be obtained in patients with
fever or with other signs of infection without fever. Radiologic
StudiesChest x-ray films may reveal signs of pneumonia and/or a
prominent mediastinal mass in some cases of T-cell acute
lymphoblastic leukemia (ALL). Computed tomography (CT) scans can
further define the degree of lymphadenopathy in some patients,
including those with mediastinal masses. MUGA Scanning and
ElectrocardiographyMultiple-gated acquisition (MUGA) scans or
electrocardiograms (ECGs) are needed when the diagnosis of acute
lymphoblastic leukemia (ALL) is confirmed, because many
chemotherapeutic agents used in the treatment of acute leukemia are
cardiotoxic. An ECG is recommended before the initiation of
treatment.Bone Marrow Aspiration and BiopsyBone marrow aspiration
and biopsy are the definitive diagnostic tests to confirm the
diagnosis of leukemia. Immunophenotyping helps to elucidate the
subtype. Aspiration slides should be stained for morphology with
either Wright or Giemsa stain. The diagnosis of acute lymphoblastic
leukemia (ALL) is made when at least 30% lymphoblasts
(French-American-British [FAB] classification) or 20% lymphoblasts
(World Health Organization [WHO] classification) are present in the
bone marrow and/or peripheral blood. In addition, slides should be
stained with myeloperoxidase (MPO) (or Sudan black) and terminal
deoxynucleotidyl transferase (TdT), unless another method is used,
such as flow cytometry. Bone marrow samples should also be sent for
flow cytometry and cytogenetics. Approximately 15% of patients with
ALL have a t(9;22) translocation (ie, Philadelphia [Ph]
chromosome), but other chromosomal abnormalities may also occur,
such as t(4;11), t(2;8), and t(8;14). Histologic FeaturesThe older,
traditional classification of acute lymphoblastic leukemia (ALL) is
the French-American-British (FAB) classification. This has now been
replaced by the newer World Health Organization (WHO)
classification but the FAB system is listed for historical
purposes, as follows: 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 with multiple
nucleoli, moderate deep blue cytoplasm, and cytoplasmic
vacuolization that often overlies the nucleus (most prominent
feature); subtype represents 1-2% of adult cases The WHO classifies
the L1 and L2 subtypes of ALL as either precursor B lymphoblastic
leukemia/lymphoblastic lymphoma (see the following image) or
precursor T lymphoblastic leukemia/lymphoblastic lymphoma depending
on the cell of origin. The L3 subtype of ALL is included in the
group of mature B-cell neoplasms, as the subtype Burkitt
lymphoma/leukemia. Diagnostic workup of a patient with preB-cell
acute lymphoblastic leukemia. Bone marrow aspiration revealed
French-American-British L2 morphology. ImmunohistochemistryA
negative myeloperoxidase (MPO) stain and a positive and terminal
deoxynucleotidyl transferase (TdT) is the hallmark of the diagnosis
of most cases of acute lymphoblastic leukemia (ALL). However,
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 some types of myeloid leukemia (eg, M0), which
also stain negative with myeloperoxidase. Flow Cytometry and
CytogeneticsAlthough more than 95% of cases of the L1 or L2 subtype
of acute lymphoblastic leukemia (ALL) are positive for Terminal
deoxynucleotidyl transferase (TdT), TdT is not specific for ALL;
TdT is absent in L3 (mature B-cell) ALL. However, TdT helps to
distinguish ALL from malignancies of more mature lymphocytes (ie,
non-Hodgkin lymphoma [NHL]). In cases of acute leukemia that are
myeloperoxidase (MPO) negative and TdT positive, the distinction
between acute myelogenous leukemia (AML) and ALL is made on the
basis of flow cytometry results. Patients with AML demonstrate
myeloid markers such as CD33, whereas patients with ALL demonstrate
lymphoid markers. Further confusion arises because some patients
with ALL have aberrant expression of myeloid markers, such as CD13.
However, if the cells are TdT positive, MPO negative, CD33
negative, and demonstrate lymphoid markers, the leukemia is
considered ALL. See an example of a flow cytometry study below.
Diagnostic workup of a patient with preB-cell acute lymphoblastic
leukemia. Flow cytometry shows that the cells were positive for
CD10, CD19, CD22, CD34, and terminal deoxynucleotidyl transferase.
Cytogenetic abnormalities occur in approximately 70% of cases of
ALL in adults (see Table 2, below). These abnormalities include
balanced translocations as occur in cases of AML. However,
abnormalities of chromosome number (hypodiploidy, hyperdiploidy)
are more common in ALL than in AML. Table 2. Common Cytogenetic
Abnormalities in ALL (Open Table in a new window)AbnormalityGenes
Involved3-Year Event-Free Survival
t(10;14)(q24;q11)HOX11/TCRA75%
6qUnknown47%
14q11TCRA/TCRD42%
11q23MLL18-26%
9pUnknown22%
12TEL20%
t(1;19)(q23;p13)PBX1/E2A20%
t(8;14)(q24;q32)
t(2;8)(p12;q24)
t(8;22)(q24;q11)
c-myc/IGH
IGK/c-myc
c-myc/IGL
17%*
80%
t(9;22)(q34;q11)bcr-abl5-10%*
66%
t(4;11)(q21;q23)AF4-MLL0-10%
* Traditional regimens.
Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin
[Adriamycin], dexamethasone) with rituxan.
Hyper-CVAD with imatinib.
Eighty-five percent of cases of ALL are derived from B cells.
The primary distinction is among the following (see also Table 3,
below): Early (pro-B) ALL, which is TDT positive, CD10 (CALLA)
negative, surface immunoglobulin (Ig) negative Precursor B ALL,
which is TDT positive, CD10 (CALLA) positive, surface Ig negative
Mature B cell (Burkitt) ALL, which is TdT negative, surface Ig
positive. Fifteen percent of these cases are derived from T cells.
Table 3. Immunophenotyping of ALL Cells ALL of B-Cell Lineage (85%
of cases of adult ALL) (Open Table in a new window)ALL
CellsTdTCD19CD10CyIgSIg
Early B-precursor ALL++---
PreB-cell ALL ++++-
B-cell ALL-++/-+/-+
ALL = acute lymphoblastic leukemia; Cylg = Cytoplasmic
immunoglobulin; SIg =Surface immunoglobulin; TdT = terminal
deoxynucleotidyl transferase.
These cases are subclassified into different stages
corresponding to the phases of normal thymocyte development. The
early subtype is surface CD3 negative, cytoplasmic CD3 positive,
and either double negative (CD4-, CD8-) or double positive (CD4+,
CD8+). The latter subtype is surface CD3 positive, CD1a negative,
and positive for either CD4 or CD8, but not both. See Table 4,
below. Table 4. Immunophenotyping of ALL Cells ALL of T-Cell
Lineage (15% of cases of adult ALL) (Open Table in a new window)ALL
CellsTdTSurface CD3CD4/CD8
Early T-precursor ALL+-+/+ or -/-
T-cell ALL+++/- or -/+
Polymerase Chain Reaction or CytogenicsStudies for bcr-abl
analysis by polymerase chain reaction (PCR) or cytogenetics may
help distinguish patients with Philadelphia chromosomepositive
acute lymphoblastic leukemia (Ph+ ALL) from those with the lymphoid
blastic phase of chronic myelogenous leukemia (CML). Most patients
with Ph+ ALL have the p190 type of bcr-abl, whereas patients with
lymphoid blastic CML have the p210 type of bcr-abl. Gene Expression
ProfilingNewer studies are analyzing ALL subtypes by gene
expression profiling. In children with ALL, Bogni et al
distinguished three groups of patients.[8] Interestingly, one of
these groups had a significantly increased risk of developing
treatment-related acute myelogenous leukemia (AML) following
chemotherapy for their ALL. Approach ConsiderationsAcute
lymphoblastic leukemia (ALL) is best treated by physicians who have
significant experience in the treatment of patients with acute
leukemia. In addition, these patients should receive treatment in a
setting where appropriate supportive care measures (high-level
blood banking and leukapheresis) are available. 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.
Traditionally, the four components of ALL treatment are induction,
consolidation, maintenance, and central nervous system (CNS)
prophylaxis; these are briefly reviewed in the following sections.
Other aspects of treatment are also discussed. See also Acute
Lymphoblastic Leukemia Treatment Protocols.Patients with ALL
require hospital admission for induction chemotherapy, and they
require readmission for consolidation chemotherapy or for the
treatment of toxic effects of chemotherapy. Surgical intervention
may be required for the placement of a central venous catheter,
such as a triple lumen, Broviac, or Hickman catheter. 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.
Induction ChemotherapyStandard induction therapy typically involves
either a four-drug regimen of vincristine, prednisone,
anthracycline, and cyclophosphamide or L -asparaginase or a
five-drug regimen of vincristine, prednisone, anthracycline,
cyclophosphamide, and L -asparaginase given over the course of 4-6
weeks. Using this approach, complete remissions (CRs) are obtained
in 65-85% of patients.The rapidity with which a patient's disease
enters CR correlates with treatment outcome. Several studies have
shown that patients whose disease is in CR within 4 weeks of
therapy have longer disease-free survival and overall survival than
those whose disease enters remission after 4 weeks of treatment. In
a large French study, patients with greater than 5% blasts in their
bone marrow on day 15 had a lower response rate (34% vs 91%), worse
disease-free survival, and worse overall survival than patients
with low blast counts on day 15.[9] Consolidation TherapyThe use of
consolidation chemotherapy in acute lymphoblastic leukemia (ALL) is
supported by several studies. Fiere et al compared consolidation
therapy with daunorubicin and cytosine arabinoside (Ara-C) versus
no consolidation therapy in adults with ALL, demonstrating a 38%
3-year, leukemia-free survival rate for subjects receiving
consolidation and maintenance therapy compared with 0% for those
receiving maintenance therapy without consolidation.[10] In a study
reported by Hoelzer et al, subjects whose disease was in remission
after induction received consolidation therapy consisting of
dexamethasone, vincristine, and doxorubicin, followed by
cyclophosphamide, Ara-C, and 6-thioguanine beginning at week
20.[11] Subjects also received maintenance therapy with
6-mercaptopurine and methotrexate during weeks 10-20 and 28-130.
The median remission of 20 months was among the longest reported at
the time. In the United Kingdom Acute Lymphoblastic Leukemia XA
study, subjects were randomized to receive early intensification
with Ara-C, etoposide, thioguanine, daunorubicin, vincristine, and
prednisone at 5 weeks; late intensification with the same regimen
at 20 weeks; both; or neither.[12] The disease-free survival rates
at 5 years were 34%, 25%, 37%, and 28%, respectively. These data
suggest a benefit to early, rather than late, intensification.[12]
A study by the Cancer and Leukemia Group B (CALGB) did not show a
benefit to consolidation therapy. Subjects whose disease was in
complete remission were randomized to receive maintenance therapy
or intensification with 2 courses of Ara-C and daunorubicin
followed by maintenance. Remission duration and overall survival
were not affected by the randomization. Because most studies have
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. Maintenance TherapyThe effectiveness of
maintenance chemotherapy in adults with acute lymphoblastic
leukemia (ALL) has not been studied in a controlled clinical trial.
However, several phase II studies without maintenance therapy have
shown inferior results compared with historical controls. A Cancer
and Leukemia Group B (CALGB) study of daunorubicin or mitoxantrone,
vincristine, prednisone, and methotrexate induction followed by
four intensifications and no maintenance was closed early because
the median remission duration was shorter than in previous
studies.[13] A Dutch study using intensive postremission
chemotherapy, three courses of high-dose Ara-C in combination with
amsacrine (course 1), mitoxantrone (course 2), and etoposide
(course 3), without maintenance, also yielded inferior results.[14]
Although maintenance appears necessary, using a more intensive
versus less intensive regimen does not appear to be beneficial.
Intensification of maintenance therapy from a 12-month course of a
four-drug regimen compared with a 14-month course of a seven-drug
regimen did not show a difference in disease-free survival between
the two groups.[15] CNS ProphylaxisIn contrast to patients with
acute myelogenous leukemia (AML), patients with acute lymphoblastic
leukemia (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, central nervous system (CNS)
prophylaxis with intrathecal chemotherapy is essential. Cortes et
al analyzed the prevalence of CNS leukemia in four consecutive
clinical trials at the MD Anderson Cancer Center and found that
that high-dose systemic chemotherapy reduces CNS relapse. However,
early intrathecal chemotherapy is necessary to achieve the lowest
risk of CNS relapse.[16] CNS relapse rates were 31% for group 1
(standard chemotherapy, no CNS prophylaxis), 18% for group 2
(high-dose systemic chemotherapy, no CNS prophylaxis), 17% for
group 3 (high-dose systemic chemotherapy, intrathecal chemotherapy
for high-risk subjects after achieving remission), and 3% for group
4 hyperfractionated cyclophosphamide, vincristine, doxorubicin, and
dexamethasone (hyper-CVAD).[16] All subjects received intrathecal
chemotherapy starting in induction. High-risk subjects received 16
intrathecal treatments, and low-risk subjects received four
intrathecal treatments. Newer Induction ApproachesStandard
induction regimens are modeled after pediatric programs and 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, more intensive induction
approaches are used by many physicians. Two notable examples are
the Memorial Acute Lymphoblastic Leukemia2 (ALL-2) protocol and the
hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and
dexamethasone) protocol. ALL-2 protocolThe ALL-2 protocol uses an
intensive, high-dose, mitoxantrone-based, acute myelogenous
leukemia (AML)-style induction regimen. In a phase I study of
high-dose mitoxantrone combined with high-dose cytosine arabinoside
(Ara-C), Arlin et al reported that all eight patients newly
diagnosed with ALL and eight of 10 patients with ALL who relapsed
achieved complete remission (CR).[17] Weiss et al reported
treatment of 37 subjects with newly diagnosed ALL with this
induction regimen followed by a first consolidation with
vincristine, prednisone, L -asparaginase, and methotrexate; a
second consolidation with Ara-C and etoposide; and then 2 years of
maintenance therapy.[18] Of these subjects, 84% achieved CR. The
median remission duration was 17 months, and median survival was 20
months.[18] In a randomized phase III trial comparing the ALL-2
regimen with the L-20 regimen (vincristine, prednisone,
cyclophosphamide and doxorubicin), the CR rate was 83% for patients
receiving ALL-2 compared with 70% for patients receiving L-20.[19]
Overall survival at 4 years was superior for patients receiving
ALL-2 (40%) versus those receiving L-20 (22%). Hyper-CVAD
regimenThe hyper-CVAD regimen is based on the success achieved with
short-term, dose-intensive chemotherapy regimens in children. It
incorporates hyperfractionated cyclophosphamide and intensive doses
of Ara-C and methotrexate in combination with dexamethasone and
vincristine. Maintenance therapy with prednisone, vincristine
(Oncovin), methotrexate, and mercaptopurine (Purinethol) (ie, POMP
protocol) is given to patients with nonmature B-cell ALL. From
1992-2000, 288 patients received hyper-CVAD at MD Anderson Cancer
Center, which 17% of patients had the Philadelphia (Ph) chromosome,
and 13% had T-cell ALL.[20] Overall, 92% of patients obtained a CR.
The 5-year survival and percentage of patients in CR at 5 years
were both 38%. Patients with Ph+ ALL had a 92% CR rate but only a
12% 5-year survival. Patients with T-cell ALL had a 75% CR rate and
a 48% 5-year survival. Patients with Burkitt ALL had a 93% CR rate
and a 67% 5-year survival.[20] Newer modifications of the
hyper-CVAD regimen include the addition of imatinib to patients
whose leukemia is Philadelphia chromosome positive, and rituxan to
patients whose leukemia is CD20 positive. Both of these approaches
have resulted in improvements in disease-free survival (see below).
Treatment of Mature B-Cell ALLMature B-cell acute lymphoblastic
leukemia (ALL) is a special type, representing only 5% of adult
patients with ALL. The hallmark of mature B-cell ALL is the
presence of surface immunoglobulin on the lymphoblasts. Using
conventional regimens, only 30-40% of patients enter complete
remission (CR) and few patients survive long term. Newer short-term
intensive therapies show improved results. A report of the
hyper-CVAD regimen showed that disease in 93% of subjects entered
CR, median survival was 16 months, and disease in 67% of subjects
alive at 5 years. In a report by Hoelzer et al, with the use of
regimens containing intensive cyclophosphamide and intermediate
methotrexate or ifosfamide and high-dose methotrexate, CR rates
were 63% (cyclophosphamide + intermediate methotrexate) and 74%
(ifosfamide + high-dose methotrexate).[21] Disease-free survival
rates increased to 50% in the first group and 71% in the second
group, and overall survival increased to 50% compared with 0% for
historical controls.[21] Although previously these patients were
referred for transplantation in first remission, many physicians
now defer transplantation for the time of relapse because of these
improved results. Burkitt ALL cells are CD20 positive. This allows
for the addition of targeted therapy with rituximab. Many studies
are have demonstrated improved efficacy, including prolonged
survival, when rituximab is added to chemotherapy in these
patients. The combination of hyper-CVAD (hyperfractionated
cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus
rituxan resulted in an overall 3-year survival of 80% compared with
50% for historical controls treated without rituxan.[22] Treatment
of Ph ChromosomePositive ALLIn the past, Philadelphia
chromosomepositive (Ph+) acute lymphoblastic leukemia (ALL) was
treated with the same regimens as other types of ALL, with poor
results. However, the tyrosine kinase inhibitor imatinib inhibits
the bcr-abl fusion protein of Ph+ ALL and thus allows targeted
therapy of this disease. As a single agent, imatinib has limited
activity. In an early study of patients with Ph+ ALL or chronic
myelogenous leukemia (CML) in lymphoid blast crisis, only 4 of 20
patients had a complete response, and all patients progressed in
less than 6 months.[23] ImatinibThe German Multicenter ALL (GMALL)
trial conducted a randomized study of imatinib versus standard
induction therapy for patients with Ph-positive ALL older than 55
years and reported the overall complete remission (CR) rate was
96.3% in patients randomly assigned to imatinib and 50% in patients
allocated to standard chemotherapy.[24] Severe adverse events were
significantly more frequent during standard induction chemotherapy
(90% vs 39%). The estimated overall survival of all patients was
42% at 24 months, with no significant difference between the 2
cohorts.[24] The addition of imatinib to chemotherapy has resulted
in significantly improved outcomes. The addition of imatinib to
hyper-CVAD (hyperfractionated cyclophosphamide, vincristine,
doxorubicin, and dexamethasone) resulted in a 3-year disease-free
survival rate of 66% and overall survival of 55% compared with a
14% 3-year disease-free survival rate and 15% overall survival for
patients treated with hyper-CVAD without imatinib.[25] Similar
results have been reported when imatinib is added to other
chemotherapy regimens. Newer tyrosine kinase inhibitors have been
developed for patients with chronic myelogenous leukemia (CML) that
has become resistant to imatinib. These agents are also being
studied in Ph-positive ALL. Nilotinib and dasatinibNilotinib is a
tyrosine kinase inhibitor that has a higher binding affinity and
selectivity for the ABL kinase than imatinib.[26] Nilotinib has 20
to 50 times the inhibitory activity against imatinib-sensitive CML
cell lines relative to imatinib. In a phase II study in patients
with relapsed/refractory Ph-positive ALL, complete responses were
reported in 10 (24%) patients treated with nilotinib.[26] Dasatinib
is a potent, orally active inhibitor of the BCR-ABL, c-KIT and the
SRC family of kinases.[27] Dasatinib is a more potent inhibitor of
BCR-ABL and c-KIT than imatinib mesylate, and it is effective in
patients with CML that is resistant to or intolerant of imatinib.
The Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA)
presented the interim results of a prospective study of dasatinib
in patients with newly diagnosed Ph-positive ALL. Prednisone was
started 7 days before the first dasatinib administration and
continued until day 31. Dasatinib was administered for a total of
84 days. At the time of the report, all 23 patients treated showed
a complete hematologic response by day 22. Although nilotinib and
dasatinib are clearly active in Ph-positive ALL, it is likely that,
similar to the results seen with imatinib, these responses will
likely not be durable. Therefore each of these agents is currently
being studied in combination with standard chemotherapy
regimens.That said, these new tyrosine kinase inhibitors are not
without their drawbacks and adverse events. Dasatinib has been
associated with pleural effusions and pulmonary arterial
hypertension,[28] while nilotinib has been linked to biochemical
changes in liver function and QT-interval prolongation. Development
of resistance may also occur with these agents.In the GIMEMA
LAL1205 protocol, patients who had newly diagnosed Ph+ ALL received
only dasatinib (for 84 d), steroids (for the first 32 d), and
intrathecal chemotherapy as induction therapy.[29] Fifty-three
patients were able to be evaluated (median age, 53.6 y). All
patients achieved a complete hematologic remission; 49 patients
(92.5%) achieved this at day 22. Postinduction management was
decided by the investigator and included no further treatment (2
patients), tyrosine kinase inhibitor alone (19 patients), tyrosine
kinase inhibitor plus chemotherapy and/or autografting (14
patients), and allografting (18 patients). At 20 months, the
overall survival was 69.2% and disease-free survival was 51.1%.
Twenty-three patients relapsed after completing induction.
PonatinibPonatinib (Iclusig), a kinase inhibitor, was approved by
the US Food and Drug Administration (FDA) in December 2012 for
patients with Ph+ ALL that is resistant or intolerant to prior
tyrosine kinase inhibitor therapy, including those with the T315I
mutation. Because ponatinib has a high risk for thromboembolic
events, its use is restricted to patients for whom no other
tyrosine kinase inhibitor therapy is indicated.In the phase II PACE
trial, 54% of chronic-phase chronic myeloid leukemia (CML)
patients, including 70% of patients with the T315I mutation,
achieved a major cytogenetic response. In patients with advanced
disease, 52% of those with accelerated-phase CML, 31% of those with
blast-phase CML, and 41% of those with Ph+ ALL achieved a major
hematologic response to ponatinib.[30] These results confirm the
phase I cinical trial results.[31] In October 2013, at the FDAs
request, ponatinib was temporarily removed from the market because
of safety concerns. The FDA cited an increased risk for
life-threatening blood clots and severe narrowing of blood vessels.
Ponatinib was returned to the US market within 2 months, but with
new safety measures to address the risk for serious cardiovascular
and thrombotic events.The revised indications for patients with ALL
are now limited to two groups: adults with T315I-positive Ph+ ALL;
and adults with Ph+ ALL for whom no other tyrosine kinase inhibitor
therapy is indicated.[32] The revised labeling also states that the
optimal dose of ponatinib has not been determined. The recommended
starting dose remains at 45 mg PO once daily with or without food,
but additional information has been included regarding dose
decreases and discontinuations. The boxed warning has been revised
to include the risk for heart failure, including fatalities, and
the incidence of vascular occlusion (at least 27%). Treatment of
the Younger AdultOlder children and younger adults with acute
lymphoblastic leukemia (ALL) can be referred to either adult or
pediatric hematologists. Usually, the patient will receive either
an adult or pediatric regimen based on this referral pattern.
However, several studies have suggested that younger patients are
best treated on pediatric protocols. For example, in a
retrospective analysis of patients aged 15-20 years treated on
either the FRALLE 93 or LALA 94 trials, the complete remission (CR)
rate was 94% for patients receiving the pediatric regimen compared
with 83% for those receiving the adult.[33] The 5-year survival was
67% in the pediatric-regimen group and 41% in the adult-regimen
group. Patients treated on the pediatric regimen were younger (15.9
y) than those treated on the adult regimen (17.9 y); however,
prognostic factors were otherwise matched.[33] Similarly, the
Childrens Cancer Group (CCG) and CALGB performed an analysis on
patients aged 16-21 years treated on their studies and, again,
event-free and overall survival were improved for patients treated
on the CCG protocols.[34] In a study by the Programme for the Study
of Therapeutics for Haematological Malignancies (PETHEMA),
adolescents and young adults were treated with a pediatric regimen
(ALL-96), demonstrating a response to therapy that was similar to
previously reported, although a slight increase in hematologic
toxicity was observed in the adult patients.[35] The majority of
children with ALL are cured with frontline chemotherapy regimens.
Many investigators are trying to translate these results into the
adult population. Areas being studied include increased intensity
of standard agents including asparaginase, risk-adapted
chemotherapy, and evaluation of minimal disease.
TransplantationMost authorities agree that allogeneic
transplantation should be offered to young patients with high-risk
features whose acute lymphoblastic leukemia (ALL) 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 (CR) may be considered for
such investigational approaches as allogeneic transplantation with
nonmyeloablative chemotherapy (ie, mini-transplants). Previously,
patients with mature B-cell ALL would have been referred for
transplantation when their disease was in first CR; however, with
improving results from more intensive chemotherapy regimens, many
clinicians are reserving transplantation for patients who have
experienced relapse. Hematopoietic stem cell transplantation (HSCT)
seems to be a valuable option for a subgroup of infants with
mixed-lineage ALL carrying poor prognostic factors that include age
younger than 6 months and either poor response to steroids at day 8
or leukocyte levels of 300 g/L or higher.[36] Relatively few
studies have compared transplantation with chemotherapy in adults
with ALL. In a study by the Groupe Ouest-Est des Leucemies Airgues
et Maladies du Sang (GOELAMS), subjects younger than 45 years who
had a sibling donor and whose disease was in remission were
assigned to allogeneic transplantation.[37] The remaining subjects
received methylprednisolone, Ara-C, mitoxantrone, and etoposide
chemotherapy followed by autologous bone marrow transplantation
(BMT). For subjects undergoing allogeneic bone marrow
transplantation (BMT), the rate of freedom from relapse was 70% at
4 years. However, because of transplant-related complications, the
event-free survival rate was only 33%. No toxic deaths occurred in
the subjects who underwent autologous BMT. However, the event-free
survival rate was only 17% at 4 years because of a high rate of
relapse.[37] In a prospective, nonrandomized trial, the Bordeaux,
Grenoble, Marseille, Toulouse group found that the 3-year
probability of disease-free survival was significantly higher with
allogeneic BMT (68%) than with autologous BMT (26%).[38] No benefit
was observed with the addition of recombinant interleukin 2 (IL-2)
after autologous BMT. In the French Group on Therapy for Adult
Acute Lymphoblastic Leukemia study, subjects aged 15-40 years whose
disease was in CR and who had a human leukocyte antigen
(HLA)-compatible sibling donor underwent allogeneic BMT.[9] The
other subjects were randomized to receive autologous BMT or
chemotherapy. Overall, no difference in was observed in 5-year
survival between the groups.[9] However, when only high-risk
patients were considered (ie, Philadelphia chromosomepositive
(Ph+), null ALL; >35 y; white blood cell [WBC] count
>30,000/L; or time to CR > wk), allogeneic BMT proved
superior to autologous BMT or chemotherapy with respect to overall
survival rates (44% vs 20%) and disease-free survival rates (39% vs
14%).[9] Other phase 2 studies have confirmed a benefit for
high-risk patients who undergo allogeneic BMT, with as many as 50%
achieving long-term remissions. Stem cell transplantationIn the
GOELAL02 study, patients with any high-risk feature (age >35 y,
nonT-ALL, WBC >30,000, adverse cytogenetics: t[9;22], t[4;11],
or t[1;19], or no CR after induction) received either allogeneic or
autologous stem cell transplantation. For patients younger than 50
years, the 6-year overall survival rate was improved for patients
receiving allogeneic transplantation (75%) compared with those
receiving autologous transplantation (40%).[37] The United Kingdom
Medical Research Council Acute Lymphoblastic Leukemia joint trial
with the Eastern Cooperative Oncology Group (MRC UKALL XII/ECOG
E2993) demonstrated that matched related allogeneic
transplantations for ALL in first complete CR provide the most
potent antileukemic therapy and considerable survival benefit for
standard-risk patients. A donor versus no-donor analysis showed
that Ph-negative patients with a donor had a 5-year improved
overall survival, 53% versus 45% (P = 0.01), and that the relapse
rate was significantly lower.[39] The survival difference was
significant in standard-risk patients but not in high-risk patients
with a high nonrelapse mortality rate in the high-risk donor group.
Patients randomized to chemotherapy had a higher 5-year overall
survival (46%) than those randomized to autologous transplantation
(37%).[39] However, the transplantation-related mortality for
high-risk older patients was unacceptably high and abrogated the
reduction in relapse risk. Allogeneic transplantation can also be
effective therapy for patients who have experienced relapse after
chemotherapy. Martino et al treated 37 consecutive patients with
primary refractory or relapsed ALL with intensive salvage
chemotherapy.[40] Of the 19 patients assigned to autologous BMT, 10
did not reach transplantation, mostly because of early relapse; 9
received transplants. Of these, 1 died early and 8 experienced
relapse 2-30 months after transplantation. Of the 10 patients who
received allogeneic BMT, 4 died early and 6 were alive and free
from disease 9.7-92.6 months after the transplantation.[40] These
results are similar to those in patients in earlier stages,
indicating that transplant-related complications are increased in
the allogeneic setting. However, a significant number of patients
can be cured. Yet, although autologous transplantation is
relatively safe, it is associated with a high relapse rate, making
this modality of little use in patients with ALL. Unrelated donor
transplantationFor patients without a sibling donor, an alternative
is an unrelated donor (URD) transplant. Weisdorf et al found that
autologous BMT was associated with a lower transplant-related
mortality rate, but URD transplantations had a lower risk of
relapse.[41] In patients whose disease was in second CR, URD
transplantations resulted in a superior rate of disease-free
survival.[41] Although peripheral blood has come to be preferred to
bone marrow as the source for stem cells from unrelated donors
(about 75% of transplants), a randomized phase III trial found that
peripheral-blood stem cells did not yield improved survival as
compared with bone-marrow cells and were significantly associated
with chronic graft-vs-host disease (GVHD)[42, 43] ; the authors
suggested that peripheral-blood stem cells might be appropriate for
patients at higher risk for graft failure and bone-marrow cells for
all others.Treatment of Relapsed ALLPatients with relapsed acute
lymphoblastic leukemia (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
(cyclophosphamide, vincristine, doxorubicin, dexamethasone)
protocol and high-dose cytosine arabinoside (Ara-C)based regimens.
As noted earlier, the hyper-CVAD regimen is based on
hyperfractionated cyclophosphamide and intermediate doses of Ara-C
and methotrexate. In a study at the MD Anderson Cancer Center of 66
patients with relapsed ALL, the complete remission (CR) rate was
44% and median survival was 42 weeks. Arlin et al reported that 8
of 10 patients with relapsed ALL achieved CR with high-dose Ara-C
and high-dose mitoxantrone.[17] A similar regimen using a single
high dose of idarubicin in combination with Ara-C (the Memorial
ALL-3 protocol) resulted in CR rates of 58-78% in patients who
experienced relapse. The Italian ALL R-87 study suggested that a
small number of patients who experience relapse will survive
long-term after allogeneic bone marrow transplantation (BMT)[44] ;
however, autologous BMT is less useful because it is associated
with a high rate of relapse. Sixty-one subjects with ALL in first
relapse received induction chemotherapy with intermediate-dose
Ara-C, idarubicin, and prednisone. Subjects whose disease was in
remission were to receive consolidation chemotherapy and then BMT.
Of these subjects, 56% achieved CR; however, only nine of the
responders underwent BMT.[44] The remaining subjects did not
undergo transplantations because of either early relapse or
excessive toxicity. Of the four subjects who underwent allogeneic
BMT, three were alive and achieved remission at 22, 43, and 63
months, whereas only one of the five subjects who underwent
autologous BMT was alive.[44] In August 2012, the US Food and Drug
Administration (FDA) approved vincristine liposomal (Marqibo) for
the treatment of Philadelphia chromosome negative (Ph-) ALL in
adults. It is indicated for patients in second or greater relapse
or whose disease has progressed following two or more anti-leukemia
therapies. This product is a sphingomyelin/cholesterol
liposome-encapsulated formulation of vincristine. In a trial of 65
patients that received at least one dose of vincristine liposomal,
15.4% of the patients had CR lasting a median of 28 days.[45] In
December 2012, the FDA approved the kinase inhibitor ponatinib for
Ph+ ALL that is resistant or intolerant to prior tyrosine kinase
inhibitor therapy. For more information, see Treatment of Ph
ChromosomePositive ALL.Blinatumomab (Blincyto), a bispecific T-cell
engager (BiTE) antibody, was approved by the FDA in December 2014
for Ph- relapsed or refractory B-cell precursor ALL. Its approval
was based on results of a Phase 2, multicenter, single-arm
open-label study. Eligible patients were >18 years of age with
Ph- relapsed or refractory B-cell precursor ALL. Of the 185
patients evaluated in the trial, 41.6% (77/185; 95% CI: 34.4-49.1)
achieved complete remission or complete remission with partial
hematologic recovery (Cr/CRh) within 2 cycles of treatment with
blinatumomab, which was the primary endpoint of the study. The
majority of responses (81% [62/77]) occurred within the first cycle
of treatment. Among patients who achieved CR/CRh, 39% (30/77) went
on to HSCT, and 75.3% (58/77 95% CI: 64.2-84.4) achieved minimal
residual disease (MRD) response, a measure of eradication of
residual disease at the molecular level.[46, 47] Novel and
Experimental Drug TherapiesA number of new drugs are in development
for the treatment of acute lymphoblastic leukemia (ALL).Clofarabine
is a novel nucleoside analogue that is approved for the treatment
of pediatric patients with refractory or relapsed ALL.[48] This
agent inhibits DNA synthesis at both DNA polymerase I and at RNA
reductase. Overall response rates average 25%. 506U78 (nelarabine
[Arranon]) is a novel purine nucleoside that is a prodrug of
guanine arabinoside (ara-G).[49] This agent was approved as an
orphan drug by the US Federal Drug Administration (FDA) in October
2005. Complete responses have been reported in 31% of patients and
in 54% of patients with T-cell ALL. The dose-limiting toxicity of
this drug is neurotoxicity.[49] Supportive Care - Blood
ProductsPatients with acute lymphoblastic leukemia (ALL) 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-relatedgraft 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 central
nervous system 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 (PT). Cryoprecipitate is
given if the fibrinogen level is less than 100 g/dL. Supportive
Care - Therapy and Prophylaxis for InfectionAntibiotics 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 antibiotic agents are added to
treat specific documented or possible infections. Patients with
persistent fever after 3-5 days of antibacterial antibiotics should
have an antifungal antibiotic (liposomal or lipid complex
amphotericin, new generation azole or echinocandin) added to their
regimen. Patients with sinopulmonary complaints would receive
anti-Aspergillus treatment. 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 the following: Ciprofloxacin (oral [PO] 500 mg twice daily
[bid]) Fluconazole (200 mg PO daily), itraconazole (200 mg PO bid),
or posaconazole (200 mg PO three times daily [tid]) Acyclovir (200
mg PO 5 times/d) or valacyclovir (500 mg PO daily)Once patients
taking these antibiotics become febrile, they are switched to
intravenous antibiotics.Supportive Care - Growth FactorsThe use of
granulocyte colony-stimulating factor (G-CSF) during induction
chemotherapy for acute lymphoblastic leukemia (ALL) is supported by
several studies. In a randomized phase 3 trial conducted by
Ottoman, 76 subjects received either G-CSF or no growth factor with
the induction chemotherapy (ie, cyclophosphamide, cytosine
arabinoside (Ara-C), 6-mercaptopurine, intrathecal methotrexate,
and cranial irradiation). The median duration of neutropenia was 8
days in subjects receiving G-CSF versus 12 days in subjects
receiving no growth factor, and the prevalence of nonviral
infections was decreased by 50% in subjects receiving G-CSF. No
difference in disease-free survival was observed between the 2
groups. In a randomized phase III study reported by Geissler et al,
subjects who received G-CSF beginning on day 2 of induction
chemotherapy (ie, with daunorubicin, vincristine, L -asparaginase,
and prednisone) had a marked decrease in the proportion of days
with neutropenia of less than 1000/L (29% for G-CSF vs 84% for
controls), a reduction in the prevalence of febrile neutropenia
(12% vs 42% in controls), and a decrease in the prevalence of
documented infections (40% vs 77%) relative to those who received
chemotherapy without G-CSF.[50] No difference was observed in
response, remission duration, or survival between the 2 groups.[50]
In the Cancer and Leukemia Group B (CALGB) 9111 study, subjects who
received G-CSF beginning on day 4 of induction chemotherapy had
significantly shorter durations of neutropenia and significantly
fewer days of hospitalization compared with those in the group that
received placebo.[51] In this study, subjects receiving G-CSF also
had higher complete remission (CR) rates, because fewer deaths
occurred during remission induction. Again, no significant effect
on disease-free survival or overall survival was observed.[51] The
importance of the early use of G-CSF FOR ALL was demonstrated by
the study of Bassan et al, in which subjects who received induction
chemotherapy with idarubicin, vincristine, L -asparaginase, and
prednisone and G-CSF on day 4 recovered significantly faster from
neutropenia, had fewer infectious complications, and required less
antibiotic than subjects beginning G-CSF on day 15.[52] Outside of
the setting of a clinical trial, few data support the use of
granulocyte-macrophage colony-stimulating factor (GM-CSF) in
patients with ALL. The GOELAMS investigators randomly assigned 67
subjects to receive GM-CSF or placebo during induction chemotherapy
with idarubicin, methylprednisolone, and high-dose Ara-C and
observed no difference in the CR rate, the duration of neutropenia,
or days with fever for the two groups.[53] In addition, mucositis
of higher than grade 3 was reduced in subjects receiving GM-CSF
(two of 35 patients vs six of 29 patients, respectively.[53] In a
Groupe d'Etude et de Traitement de la Leucemie Aigue
Lymphoblastique de l'Adulte (GET-LALA) study, in patients who
received G-CSF, GM-CSF, or no growth factor during induction
therapy, the median time for neutrophil recovery was 17 days for
G-CSF, 18 days for GM-CSF, and 21 days for no growth factors.[54]
Hyperuricemia and Tumor Lysis SyndromeTumor lysis syndrome is a
potentially life-threatening complication that may be seen in
patients receiving chemotherapy for acute leukemias and high-grade
non-Hodgkin lymphomas. This syndrome is characterized by elevated
blood levels of uric acid, phosphate, and potassium; decreased
levels of calcium; and acute renal failure. As mentioned earlier,
patients with a high tumor burden, particularly those with severe
hyperuricemia, can present in renal failure. Allopurinol at 300 mg
1-3 times per day is recommended during induction therapy until
blasts are cleared and hyperuricemia resolves. High-risk patients
(those with very high lactate dehydrogenase [LDH] or leukemic
infiltration of the kidneys) can benefit from rasburicase. In a
study by Cortes et al, adults with hyperuricemia or those at high
risk for tumor lysis syndrome not only had an improved plasma uric
acid response rate with rasburicase alone (0.20 mg/kg/d
intravenously [IV], days 1-5) (87%) or in combination with
allopurinol (IV rasburicase 0.20 mg/kg/d, days 1-3, followed by
oral [PO] allopurinol 300 mg/d, days 3-5) (78%) than with
allopurinol alone (300 mg/d PO, days 1-5) (66%), but they also had
more rapid control of their plasma uric acid with rasburicase alone
(4 h) or with allopurinol (4 h) than with allopurinol alone (27
h).[55] Long-Term Monitoring Patients with acute lymphoblastic
leukemia (ALL) are monitored on an outpatient basis for disease
status and the effects of chemotherapy. Maintenance therapy for
these patients is also administered in an outpatient setting. In
addition, all patients should be on trimethoprim-sulfamethoxazole
(TMP-SMZ) to prevent Pneumocystis jiroveci pneumonia, and patients
may benefit from receiving oral nystatin or clotrimazole troches to
reduce the risk of candidiasis. Patients with a high risk of
relapse may also need additional antifungal therapy, such as
itraconazole. Medication SummaryAntineoplastic agents are used for
induction, consolidation, and maintenance therapy and central
nervous system (CNS) prophylaxis in patients with acute
lymphoblastic leukemia (ALL). Those medications cause severe bone
marrow depression, and only physicians specifically trained in
their use should administer them. In addition, access to
appropriate supportive care is required.Other drug classes used in
treatment of ALL include the following: Corticosteroids may be used
during induction, consolidation, and/or maintenance therapy
Tyrosine kinase inhibitors are used in treatment of Philadelphia
chromosome positive (Ph+) ALL Colony-stimulating factors are used
to treat or prevent neutropenia and to mobilize autologous
peripheral blood progenitor cells for bone marrow transplantation
(BMT) and in management of chronic neutropenia Prophylactic
antibiotics and antifungal drugs are given to prevent infection in
patients receiving chemotherapyCorticosteroidsClass
SummaryCorticosteroids may be used during induction, consolidation,
and/or maintenance therapy for acute lymphoblastic leukemia
(ALL).View full drug informationPrednisonePrednisone is a
corticosteroid that has a wide range of activities. In ALL, this
agent is used because of its direct antileukemic effects. View full
drug informationDexamethasone (Baycadron, Maxidex,
Ozurdex)Dexamethasone is another corticosteroid that acts as an
important chemotherapeutic agent in the treatment of ALL. Like
prednisone, this agent is used in induction and reinduction therapy
and is also given as intermittent pulses during continuation
therapy. AntineoplasticsClass SummaryAntineoplastic agents are used
for induction, consolidation, maintenance, and central nervous
system (CNS) prophylaxis. Cancer chemotherapy is based on an
understanding of tumor cell growth and how drugs affect this
growth. After cells divide, they enter a period of growth (ie,
phase G1), followed by DNA synthesis (ie, phase S). The next phase
is a premitotic phase (ie, G2), then, finally, a mitotic cell
division (ie, phase M). Cell-division rates vary for different
tumors. Most common cancers grow slowly compared with normal
tissues, and the rate may be decreased in large tumors. This
difference allows normal cells to recover from chemotherapy more
quickly than malignant ones and is the rationale behind current
cyclic dosage schedules. Antineoplastic agents interfere with cell
reproduction. Some agents act at specific phases of the cell cycle,
whereas others (ie, alkylating agents, anthracyclines, cisplatin)
are not phase specific. Cellular apoptosis (ie, programmed cell
death) is another potential mechanism of many antineoplastic
agents. View full drug informationVincristine (Vincasar
PFS)Vincristine is a vinca alkaloid agent that acts by arresting
cells in metaphase.View full drug informationVincristine liposomal
(Marqibo)A sphingomyelin/cholesterol liposome-encapsulated
formulation of vincristine. Indicated for treatment of Ph-negative
ALL for patients in second or greater relapse or whose disease has
progressed following 2 or more antileukemia therapies. View full
drug informationAsparaginase Erwinia chrysanthemi
(Erwinaze)Catalyzes deamidation of asparagine to aspartic acid and
ammonia, thereby reducing circulating levels of asparagine. Lack of
asparagine synthetase activity results in cytotoxicity specific for
leukemic cells that depend on an exogenous source of the amino acid
asparagine. Indicated as part of a multiagent chemotherapeutic
regimen as a substitute for asparaginase (Elspar), which was
discontinued by the manufacturer in August 2012. View full drug
informationPegaspargase (Oncaspar, PEG L Asparaginase)Modified
version of L-asparaginase. Selective killing of leukemic cells it
thought to be due to depletion of plasma asparagine, the amino acid
required for protein synthesis. It is indicated as a component of a
multi-agent chemotherapeutic regimen for the first line treatment
of ALL. It is also indicated for use in patients with
hypersensitivity to native forms of L-asparaginase. View full drug
informationMethotrexate (Trexall)Methotrexate is an antimetabolite
of the folic acid analogue type. This agent inhibits dihydrofolate
reductase, resulting in inhibition of DNA synthesis, repair, and
cellular replication. View full drug informationMercaptopurine
(Purinethol)Mercaptopurine is antimetabolite of the purine analogue
type. Its primary effect is inhibition of DNA synthesis.View full
drug informationCyclophosphamideCyclophosphamide is an alkylating
agent of the nitrogen mustard type that acts by inhibiting cell
growth and proliferation.View full drug
informationCytarabineCytosine arabinoside is an antimetabolite that
induces activity as a result of activation to cytarabine
triphosphate and includes inhibition of DNA polymerase and
incorporation into DNA and RNA. View full drug
informationDaunorubicin (Cerubidine)Daunorubicin is an
anthracycline that inhibits topoisomerase II. This agent also
inhibits DNA and RNA synthesis by intercalating between DNA base
pairs. View full drug informationIdarubicin (Idamycin)Idarubicin is
a topoisomerase II inhibitor that inhibits cell proliferation by
inhibiting DNA and RNA polymerase.View full drug
informationMitoxantrone (Novantrone)Mitoxantrone is also a
topoisomerase II inhibitor. This agent inhibits cell proliferation
by intercalating DNA and inhibiting topoisomerase II. View full
drug informationDasatinib (Sprycel)Dasatinib is a multiple tyrosine
kinase inhibitor that inhibits the growth of cell lines
overexpressing BCR-ABL. This agent is indicated for Philadelphia
chromosomepositive acute lymphoblastic leukemia (Ph+ ALL) in
individuals with resistance to or who were intolerant of previous
therapy. View full drug informationNelarabine (Arranon)Nelarabine
is a prodrug of the deoxyguanosine analogue
9-beta-D-arabinofuranosylguanine (ara-G) that is converted to the
active 5'-triphosphate, ara-GTP, a T-cellselective nucleoside
analogue. Leukemic blast cells accumulate ara-GTP, which allows for
incorporation into DNA, leading to inhibition of DNA synthesis and
cell death.This agent is approved by the US Food and Drug
Administration (FDA) as an orphan drug to treat persons with T-cell
ALL whose disease has not responded to or which has relapsed with
at least 2 chemotherapy regimens.View full drug
informationClofarabine (Clolar)Clofarabine is a purine nucleoside
antimetabolite that inhibits DNA synthesis and is indicated for
relapsed or refractory acute lymphoblastic leukemia in pediatric
patients. Pools of cellular deoxynucleotide triphosphate are
decreased by inhibiting ribonucleotide reductase and terminating
DNA chain elongation and repair. This agent also disrupts
mitochondrial membrane integrity. It is indicated for the treatment
of patients aged 1-21 years who have relapsed or refractory acute
ALL. For adults older than 21 years, base dosing on surface area as
in pediatrics. Clofarabine is not indicated for adults older than
21 years. Tyrosine Kinase InhibitorsClass SummaryPhiladelphia
chromosome-positive (Ph+) ALL is treated with tyrosine kinase
inhibitors. These agents provide targeted therapy by inhibiting the
BCR-ABL fusion protein. View full drug informationImatinib
(Gleevec)Imatinib is indicated for relapsed or refractory Ph+ ALL.
It is also indicated for newly diagnosed PH+ CML in chronic phase
and for Ph+ CML in blast crisis, accelerated phase, or chronic
phase after failure of interferon-alpha therapy. View full drug
informationNilotinib (Tasigna)Nilotinib is indicated for newly
diagnosed Ph+ CML in chronic phase and for the treatment of Ph+ CML
(chronic phase, accelerated phase) in patients resistant or
intolerant to prior therapy including imatinib. View full drug
informationDasatinib (Sprycel)Dasatinib is indicated for Ph+ ALL
with resistance or intolerance to prior therapy. It is also
indicated for newly diagnosed Ph+ CML in chronic phase, CML
(chronic, accelerated, or plast phase Ph+) with resistance or
intolerance to prior therapy including imatinib. View full drug
informationPonatinib (Iclusig)Ponatinib is a kinase inhibitor
indicated for patients with CML or Ph+ ALL that is resistant or
intolerant to prior tyrosine kinase inhibitor therapy, including
those with the T315I mutation. Because ponatinib has a high risk
for thromboembolic events, its use is restricted for patients whom
no other TKI therapy is indicated. Bispecific T-Cell Engager (BiTE)
AntibodiesClass SummaryBispecific T cell engager antibodies are a
type of immunotherapy that assists the body's immune system to
detect and target malignant cells. The modified antibodies are
designed to engage 2 different targets simultaneously, thereby
juxtaposing T cells to cancer cells, thereby helping place the T
cells within reach of the targeted cell, with the intent of
allowing T cells to inject toxins and trigger apoptosis. View full
drug informationBlinatumomab (Blincyto)Bispecific CD19-directed CD3
T-cell engager that binds to CD19 expressed on the surface of cells
of B-lineage origin and CD3 expressed on the surface of T cells. It
activates endogenous T-cells by connecting CD3 in the T-cell
receptor (TCR) complex with CD19 on benign and malignant B cells.
It is indicated for treatment of Ph- relapsed or refractory B-cell
precursor ALL. Colony-Stimulating FactorsClass
SummaryColony-stimulating factors (CSF) act as hematopoietic growth
factors that stimulate the development of granulocytes. These
agents are used to treat or prevent neutropenia when patients
receive myelosuppressive cancer chemotherapy and to reduce the
period of neutropenia that is associated with bone marrow
transplantation (BMT). Colony-stimulating factors are also used to
mobilize autologous peripheral blood progenitor cells for BMT and
in management of chronic neutropenia.View full drug
informationFilgrastim (Neupogen)Filgrastim is a granulocyte
colony-stimulating factor (G-CSF) that activates and stimulates the
production, maturation, migration, and cytotoxicity of neutrophils.
View full drug informationPegfilgrastim (Neulasta)Pegfilgrastim is
a long-acting filgrastim created by the covalent conjugate of
recombinant G-CSF (ie, filgrastim) and monomethoxypolyethylene
glycol. As with filgrastim, this agent acts on hematopoietic cells
by binding to specific cell surface receptors, thereby activating
and stimulating production, maturation, migration, and cytotoxicity
of neutrophils. AntimicrobialsClass SummaryProphylactic
antimicrobial drugs are given to prevent infection in patients
receiving chemotherapy.View full drug
informationTrimethoprim-sulfamethoxazole (Septra,
Bactrim)Trimethoprim-sulfamethoxazole (TMP-SMZ) inhibits bacterial
growth by inhibiting the synthesis of dihydrofolic acid. All
immunocompromised patients should be treated with TMP-SMZ to
prevent Pneumocystis carinii pneumonia (PCP). AntifungalsClass
SummaryThese agents may change the permeability of the fungal cell,
resulting in a fungicidal effect.View full drug
informationNystatinNystatin is used to prevent fungal infections in
mucositis. This agent is a fungicidal and fungistatic antibiotic
from Streptomyces noursei that is effective against various yeasts
and yeastlike fungi. Nystatin acts by changing the permeability of
the fungal cell membrane after binding to cell membrane sterols,
causing cellular contents to leak.Treatment with this agent should
continue until 48 hours after the symptoms disappear. Nystatin is
not substantially absorbed from the gastrointestinal tract.View
full drug informationClotrimazoleClotrimazole may be used instead
of nystatin to prevent fungal infections. It is a broad-spectrum
antifungal agent that inhibits yeast growth by altering cell
membrane permeability, causing death of fungal cells. View full
drug informationItraconazole (Sporanox)Itraconazole has fungistatic
activity and is used to prevent fungal infections in high-risk
patients. This drug is a synthetic triazole antifungal agent that
slows fungal cell growth by inhibiting CYP-dependent synthesis of
ergosterol, a vital component of fungal cell membranes. The
bioavailability of this drug is greater in the oral solution
compared with the capsule formulation.