Acute Lymphoblastic Leukemia

INTRODUCTION — Acute leukemia, the most common form of cancer in children,
comprises approximately 30 percent of all childhood malignancies, with acute lymphoblastic

leukemia (ALL) being five times more common than acute myeloid leukemia (AML) [1].
Each year in the United States approximately 2500 to 3500 new cases of ALL are
diagnosed in children. ALL incidence is slightly higher in Whites (36 cases/million) and
Hispanics (41 cases/million) than in Black Americans (15 cases/million) [2].
Survival rates for ALL have improved dramatically since the 1980s, with a current five-year
overall survival rate estimated at greater than 85 percent [1,3,4]. This improvement is in
large part because of treatment of large numbers of children with sequential collaborative
standardized research protocols [5]. Approximately 75 to 80 percent of children with newly
diagnosed ALL participate in clinical research trials, the goals of which are to improve
clinical outcome and to minimize acute toxicities and late-occurring adverse events.
The presentation and diagnosis of ALL in children are reviewed here. The risk group
stratification and treatment of childhood ALL are discussed separately. (See "Risk group
stratification and prognosis for acute lymphoblastic leukemia in children and
adolescents" and "Overview of the treatment of acute lymphoblastic leukemia in children
and adolescents".)
EPIDEMIOLOGY — As mentioned above, approximately 2500 to 3500 new cases of ALL

are diagnosed in children each year in the United States with an incidence of approximately
3.4 cases per 100,000 [1]. The incidence of pediatric leukemia varies worldwide but this
may be influenced, in part, by diagnostic and reporting differences [6]. ALL incidence is
slightly higher in Whites (36 cases/million) and Hispanics (41 cases/million) than in Black
Americans (15 cases/million) [2].
It appears the incidence of childhood leukemia is increasing as demonstrated by the two

following studies:
●In an analysis of the Surveillance, Epidemiology, and End Results (SEER) database,
there was a steady increase in ALL incidence from 1975 to 2010 with an average
annual increase in incidence of approximately 0.7 percent [1]. The estimated incidence
increased from 25 cases per million in 1975 to 34 cases per million in 2010.
●In a study that used data from 63 European population-based cancer registries of
children diagnosed with cancer, the incidence of leukemia including ALL increased by
an average of 1.4 percent from 1970 to 1999 [7].
●In a study from Great Britain, the incidence of leukemia (mostly attributable to ALL)
has steadily increased from 3.83 to 4.61 per 100,000 persons by sex and age from the
five-year period of 1971 to 1975 and 1996 to 2000 [8].
In contrast, a study from four Nordic countries (Denmark, Finland, Norway, and Sweden)
reported that the incidence of childhood ALL remained stable at an approximate rate of 3.3
cases per 100,000 children below 15 years of age from 1983 to 2002 after an increase in
incidence between 1975 and 1983 [9].
The peak incidence occurs between two and five years of age [1,9,10], and it occurs more
commonly among boys than girls [1,9]. The vast majority of ALL cases are not associated
with genetic or environmental risk factors. However, certain genetic and immunodeficiency
syndromes (eg, Down syndrome, neurofibromatosis type 1, Bloom syndrome, and ataxia
telangiectasia) place children at higher risk for ALL [11,12]. An increased risk of ALL
associated with higher birth weight has also been noted [13]. Studies of the relationship
between childhood ALL, urban/rural status and population density, as well as other possible
etiologic factors (eg, environmental exposures, abnormal immune response to common
infection[s]) have yielded inconsistent results [14-27].
Genomic studies have noted that somatic, polymorphic variants of ARD5B, IKZF1 (the gene
encoding Ikaros) and CDKN2A are associated with an increased risk of ALL (odds ratio 1.3
to 1.9) [28-31]. Other rare germline mutations in PAX5, ETV6, and particularly p53 can also
strongly predispose to the development of leukemia [4].
However, in most cases, childhood ALL is not considered to be a familial disease. A

Scandinavian study that included 3994 children with ALL identified 36 siblings who were
subsequently diagnosed with ALL [32]. They found that, compared with the general
population, twin siblings of children with ALL are at markedly increased risk of developing
leukemia (standardized incidence ratio [SIR] 163; 95% CI 70-320), while singleton siblings
are at only slightly increased risk (SIR 3; 95% CI 2-6). Importantly, ALL is a disease with a
low incidence in the general population (41 cases per 1 million in children ages 0 to 14
years); as a result, even a large increase in the relative risk among siblings does not
translate into a high likelihood of developing leukemia. With the current available
information, we do not recommend a screening program for siblings of patients with
leukemia. Screening of patients for familial leukemia is discussed separately. (See "Familial
acute leukemia and myelodysplastic syndromes".)
EARLY SIGNS AND SYMPTOMS — The most common presenting symptoms of ALL are
nonspecific and may be difficult to distinguish from common, self-limited diseases of
childhood. In a meta-analysis, more than half of children with childhood leukemia had at
least one of the following five features on presentation: palpable liver, palpable spleen,
pallor, fever, or bruising [33]. Unexplained persistence of any of these common signs or
symptoms should prompt consideration of malignancy as a possible cause. The
characteristics of common presenting signs or symptoms of leukemia that are suggestive of
malignancy are discussed briefly below and in more detail separately. (See "Clinical
assessment of the child with suspected cancer".)
Hepatosplenomegaly — Hepatomegaly (64 percent) and/or splenomegaly (61 percent) are

the most common clinical findings in association with childhood leukemia [33]. These
abnormalities may also manifest as symptoms of anorexia, weight loss, abdominal
distension or abdominal pain, or an abdominal mass noted by a family member or clinician.
Lymphadenopathy — Nearly half of children with ALL present with lymphadenopathy,

which is one of the indications of extramedullary leukemic spread [34]. As a general rule, a
lymph node is considered enlarged if it is >10 mm in its greatest diameter. Exceptions to
this rule include the following:
●Epitrochlear nodes are enlarged if they are >5 mm.

●Inguinal nodes are enlarged if they are >15 mm in greatest diameter.
●Cervical nodes are enlarged if they are >20 mm.
Lymphadenopathy associated with malignancy usually is nontender, firm, rubbery, and

matted. Persistent or progressive lymphadenopathy that does not respond to antibiotic
therapy suggests the need for more extensive evaluation. (See "Clinical assessment of the
child with suspected cancer", section on 'Lymphadenopathy' and "Peripheral
lymphadenopathy in children: Evaluation and diagnostic approach", section on 'Initial
evaluation'.)
Musculoskeletal pain — Although bone pain occurs commonly among children,

particularly adolescents, it may be a symptom of ALL. Early bone marrow examination
should be considered in any child who has persistent bone pain and peripheral blood
abnormalities. (See 'Diagnosis' below.)
Bone pain, particularly affecting the long bones, and caused by leukemic involvement of the
periosteum, is a presenting symptom in 21 to 38 percent of cases of acute leukemia [35-38].
Bone pain also results from aseptic osteonecrosis because of malignant cell necrosis in the
bone marrow [39,40]. Radiographic changes are present in as many as one-half of cases
[35]. Young children with such pain may present with limp or refusal to bear weight [34].
(See "Evaluation of bone marrow aspirate smears", section on 'Bone marrow necrosis'.)
Musculoskeletal pain associated with acute leukemia, particularly if it occurs in the joints,
may be mistaken for rheumatologic pain. Features that may be helpful in differentiating
leukemic from rheumatologic musculoskeletal pain are discussed separately. (See "Clinical
assessment of the child with suspected cancer", section on 'Bone and joint pain'.)
Headache — Although uncommon (<5 percent of cases), leukemia involving the central
nervous system (CNS) can present with symptoms of increased intracranial pressure,
including headache, vomiting, lethargy, and/or nuchal rigidity [41]. Rarely, leukemia can
present with cranial nerve abnormalities [42,43].
Testicular enlargement — Although rare, painless unilateral testicular enlargement can be

a presenting sign of ALL. Any persistent, painless, solid testicular mass should be referred
for biopsy by a pediatric surgeon after evaluation by ultrasound. When testicular leukemia is
suspected, bilateral wedge biopsies are preferred to decrease sampling error. Histologic
interpretation can be challenging and requires the ability to differentiate leukemic
lymphoblasts from reactive lymphocytes.
Mediastinal mass — Adolescents with ALL may present with many of the features of non-
Hodgkin lymphoma. Distinguishing between these two disorders can sometimes be difficult.
T cell ALL commonly occurs in older boys who present with high initial white blood cell
(WBC) counts and a large mediastinal mass. Patients who present with features of
lymphoma, such as mediastinal mass and lymphadenopathy, often have significant bone
marrow involvement. Malignant lymphoblasts found in T cell lymphoblastic lymphoma are
indistinguishable from T cell ALL; by convention, children having more extensive bone
marrow involvement (>25 percent in the United States) are classified as having leukemia.
(See 'Diagnosis' below and "Clinical presentation and diagnosis of non-Hodgkin
lymphoma".)
A large anterior mediastinal mass can narrow the trachea, causing respiratory distress.
Such masses can also be associated with pleural effusions, further compromising
respiratory function. In addition, a mediastinal mass can obstruct the superior vena cava,
resulting in superior vena cava syndrome, which is manifest as pain, dysphagia, dyspnea,
or swelling of the neck, face, and upper limbs. (See "Malignancy-related superior vena cava
syndrome".)
Peripheral blood abnormalities — Most children with ALL have

anemia and/or thrombocytopenia with either normal or slightly increased WBC counts, and
lymphoblasts on peripheral smear (picture 1 and picture 2) [44]. Approximately 50 percent
of children have WBC counts <10,000/microL, and 20 percent have an initial leukocyte
count >50,000/microL [34,44]. Approximately one-half of children with ALL present with
bleeding (including petechiae and purpura) and three-quarters have a platelet
count <100,000/microL at the time of diagnosis [34].
These findings suggest the need for bone marrow examination, which should be performed
for the following indications:
●Atypical cells in the peripheral blood
●Unexplained depression of more than one peripheral blood element (cytopenias).
Cytopenias are defined as an absolute neutrophil count (ANC) of <500/microL, Hgb
<8 g/dL, or a platelet count <150,000/microL.
●Unexplained lymphadenopathy or hepatosplenomegaly associated with cytopenias
PATHOLOGIC FEATURES
Morphology — In the World Health Organization classification system for hematologic

malignancies, the lymphoblastic neoplasms (which may present as
leukemia and/or lymphoma) are divided into two general categories based upon lineage
(table 1) (see "Classification of the hematopoietic neoplasms", section on 'Lymphoid
neoplasms'):
●Precursor B cell lymphoblastic leukemia/lymphoma, also called precursor B cell acute

lymphoblastic leukemia (precursor B cell ALL) (see "Clinical manifestations, pathologic
features, and diagnosis of precursor B cell acute lymphoblastic leukemia/lymphoma")
●Precursor T cell lymphoblastic leukemia/lymphoma (precursor T-LBL), also called
precursor T cell acute lymphoblastic leukemia (T cell ALL) (see "Clinical
manifestations, pathologic features, and diagnosis of precursor T cell acute
lymphoblastic leukemia/lymphoma")
These two entities are morphologically indistinguishable. On peripheral blood smears and
bone marrow aspirates, lymphoblasts vary from small cells with scant cytoplasm,
condensed nuclear chromatin, and indistinct nucleoli to larger cells with moderate amounts
of cytoplasm, dispersed chromatin, and multiple nucleoli (picture 3 and picture 4). A few
azurophilic cytoplasmic granules may be present. Auer rods are absent.
In tissue sections, the tumor cells are small to medium-sized, with scant cytoplasm, round,
oval, or convoluted nuclei, fine chromatin, and indistinct or small nucleoli (picture 5).
Occasionally patients have larger cells.
Historically, childhood ALL was classified morphologically using the French-American-

British (FAB) system that incorporates information regarding the size, amount of cytoplasm,
and prominence of nucleoli of tumor cells from the bone marrow aspirate [45]. While some
clinicians still use this system to describe the phenotype of the tumor cells, FAB morphology
has lost its prognostic value as our understanding of disease biology has improved and
treatment regimens have become more intense and successful. As such, FAB subtype is
not currently used in either diagnosis or treatment decisions. (See "Evaluation of bone
marrow aspirate smears", section on 'Acute lymphoblastic leukemia' and "Risk group
stratification and prognosis for acute lymphoblastic leukemia in children and adolescents",
section on 'Risk stratification'.)
The former FAB L3 category is currently described as Burkitt lymphoma/leukemia in the

WHO classification. (See "Epidemiology, clinical manifestations, pathologic features, and
diagnosis of Burkitt lymphoma", section on 'Pathology'.)
Immunophenotype — Leukemia cells in ALL are classified according to immunophenotype

using an extensive panel of monoclonal antibodies to cell surface "cluster of differentiation"
(CD) markers (table 2). Markers used to classify cells by lineage are the same as those
used in adult ALL. The immunologic subtype of the tumor cells is used in the risk group
stratification of childhood ALL. (See "Risk group stratification and prognosis for acute
lymphoblastic leukemia in children and adolescents", section on
'Immunophenotype' and "Clinical manifestations, pathologic features, and diagnosis of
precursor B cell acute lymphoblastic leukemia/lymphoma" and "Clinical manifestations,
pathologic features, and diagnosis of precursor T cell acute lymphoblastic
leukemia/lymphoma".)
Approximately 70 to 80 percent of cases of childhood ALL are of B-precursor lineage (ie,

precursor B cell leukemia or early pre-B cell ALL). B-precursor leukemia typically is CD10+,
CD19+, and sometimes CD20+. Leukemic lymphoblasts with the L3 morphology (described
above) usually have markers for mature B cell ALL (CDs 10 ± 19, 20, 22, 25, and surface
immunoglobulin [sIg]).
Cases of T cell ALL (ie, precursor T lymphoblastic leukemia), which comprise 15 to 17

percent of all cases of ALL, are positive for CD2, 3, 4, 5, 7, and 8. Approximately 10 percent
of those with T cell ALL have a distinct immunophenotype (CD8-, CD5dim) and gene
expression signature, consistent with an early T cell precursor phenotype (ETP ALL) [46].
Initial studies showed that these patients have a high rate of remission failure (57 to 75
percent) and a poor overall survival [47]. However, data from more recent cohorts have
shown that these patients have a more intermediate-risk outcome (five-year event-free
survival, 78 percent) when treated on high-risk contemporary protocols [48]. Whole genome
sequencing suggests that ETP ALL has many of the genetic features of myeloid stem cells
[49].
The expression of markers on the leukemic lymphoblasts does not strictly correlate with
normal lymphoid maturation. Some B-precursor ALL cells, for example, express myeloid
markers (ie, markers more typical of the granulocytic series) in addition to classic B-
lymphocyte markers. Although this does not affect long-term prognosis or risk group
assignment, it is one of the reasons why immunophenotyping should not be used as the
sole means of leukemia classification [34].
Cytogenetics — Chromosomal abnormalities are common in childhood ALL. Although not
specifically used for diagnosis, cytogenetic findings are an essential part of the risk group
stratification of childhood ALL and help to guide therapy. Standard karyotype analysis is
complemented by molecular analysis of known predictive chromosomal abnormalities using
fluorescence in situ hybridization (FISH) and other molecular techniques [50,51].
(See "Cytogenetics and molecular genetics in acute lymphoblastic leukemia" and "Tools for
genetics and genomics: Cytogenetics and molecular genetics".)
The cytogenetic abnormalities used to classify pediatric ALL are similar to those used for
adult ALL [52]. A notable exception is that the classification of childhood ALL does not
include either t(5;14)(q31;q32) nor t(1;19)(q23;p13.3) in the risk group stratification due to
their rarity and uncertain prognostic value, respectively. The following is a summary of the
genetic abnormalities used to risk stratify childhood ALL, which are discussed in greater
detail separately. (See "Risk group stratification and prognosis for acute lymphoblastic
leukemia in children and adolescents".)
Commonly recognized abnormalities associated with a poor outcome include the following
[53-62]:
●t(9;22) BCR/ABL1 translocation (Philadelphia chromosome) – Present in 3 to 4

percent of ALL patients; often occurs in older children.
●BCR/ABL1-like ALL – A small percentage of patients have a distinct gene expression
profile that is very similar to Philadelphia positive ALL, but does not contain the t(9;22)
translocation. These patients have genetic alterations that involve either an ABL kinase
or contain mutations/fusions in the JAK-STAT pathway.
●t(variable; 11q23) – Rearrangements involving the KMT2A/MLL gene are present in 5
percent of pediatric ALL patients and 60 percent of infant ALL patients.
●iAMP21 – Intrachromosomal amplification of chromosome 21.
●Extreme hyperdiploidy (59 to 84 chromosomes) or hypodiploidy (fewer than 45
chromosomes) is associated with poor outcome.
The following abnormalities are associated with a favorable prognosis [60]:
●t(12;21) ETV6/RUNX1 (formerly referred to as TEL/AML1) rearrangement in B-

precursor ALL, which occurs in 20 to 25 percent of cases of childhood ALL [63,64].
●Hyperdiploidy (54 to 58 chromosomes) – Hyperdiploidy is present in 20 to 25 percent
of childhood ALL. Children with lymphoblasts exhibiting hyperdiploidy (not extreme
hyperdiploidy) have the best prognosis, particularly if associated with the combined
trisomies of chromosomes 4 and 10 [65,66]. Trisomy of 4 and 10 is commonly used to
risk-stratify patients to less intense chemotherapy.
Cytogenetics must be considered in the context of other risk factors and response to the
first month of chemotherapy. As an example, in one prospective study of 44 children with
high-risk ALL, as determined by age, white blood cell count, and immunophenotype,
cytogenetic abnormalities did not independently predict outcome [67]. (See "Risk group
stratification and prognosis for acute lymphoblastic leukemia in children and adolescents".)
DIAGNOSTIC EVALUATION
Initial evaluation — Children who are suspected of having leukemia should be referred to
a pediatric cancer center for evaluation [68]. This evaluation will include clinical
examination, and bone marrow aspiration and biopsy, which will diagnose ALL and
determine the leukemia phenotype as well as the presence or absence of cytogenetic
abnormalities. Bone marrow aspirations are required if the patient is to be enrolled in a
cooperative group trial. Bone marrow aspirations are also preferred for diagnostic accuracy
and often provide better cytogenetics results. It is not standard in children or adolescents to
diagnose leukemia from the peripheral blood when lymphoblasts are present. However, in
cases where it is difficult to obtain either bone marrow aspirate or biopsy, peripheral blood
can be substituted for bone marrow. This initial information will be used to assign the patient
to a treatment group based upon risk stratification. (See "Risk group stratification and
prognosis for acute lymphoblastic leukemia in children and adolescents".)
The initial laboratory evaluation also includes assessment for possible disease
complications. As an example, patients with a high tumor burden may have increased
serum uric acid concentration, which can cause uric acid nephropathy and renal failure if
not addressed before chemotherapy is started. The initial laboratory evaluation should
include a complete blood count with manual differential, PT, PTT, electrolytes, uric acid, and
renal and liver function tests. Baseline viral titers, including cytomegalovirus, Epstein-Barr
virus, human immunodeficiency virus, hepatitis B virus, and varicella zoster virus often are
included.
Several abnormalities, including hepatic dysfunction, coagulation abnormalities,

hypercalcemia, hypocalcemia, hyperkalemia, and hyperphosphatemia, may be noted [34].
(See "Overview of the treatment of acute lymphoblastic leukemia in children and
adolescents", section on 'Adverse effects'.)
Diagnosis — The diagnosis and classification of leukemia are based upon specialized tests
that are performed on cells derived from a bone marrow aspirate or tissue biopsy
specimens. When clinical circumstances preclude bone marrow examination, the diagnosis
can be made from cells obtained from the peripheral blood or pleural effusions. The exact
peripheral blood minimum blast percentage has also not been defined for an accurate
diagnosis in pediatrics. (See "Clinical manifestations, pathologic features, and diagnosis of
precursor T cell acute lymphoblastic leukemia/lymphoma", section on
'Diagnosis' and "Clinical manifestations, pathologic features, and diagnosis of precursor B
cell acute lymphoblastic leukemia/lymphoma", section on 'Diagnosis'.)
The diagnosis of central nervous system (CNS) leukemia requires one of the following:
●Cytologic confirmation of the presence of leukemic cells in the cerebrospinal fluid

(CSF)
●Clinical signs of CNS leukemia such as facial nerve palsy, brain/eye involvement, or
hypothalamic syndrome
●A tumor mass involving the CNS as determined by imaging studies
ALL can present clinically as either a mass lesion or as leukemia. Although the distinction in
some patients is arbitrary, ALL is the preferred term in the US when the bone marrow
contains more than 25 percent lymphoblasts, whereas lymphoma is the preferred term
when the process is confined to a mass lesion with minimal or no blood and bone marrow
involvement [69].
CNS involvement is often categorized into three groups:
●CNS1 – no blasts in the CSF

●CNS2 – <5 blasts in the CSF with or without RBC
●CNS3 – >5 blasts in CSF
It was initially thought that patients with low levels of CSF leukemia involvement (CNS2) did
as well as those with no CNS disease. However, with improvement in current treatment
regimens, it has become evident that patients with only low levels of leukemia have a lower
event-free survival, largely due to an increased rate of CNS relapse [70]. Although
controversial, many institutions elect to treat patients with CNS2 disease with more
aggressive CNS regimens.
Differential diagnosis — As noted above, the presenting signs and symptoms of ALL are
nonspecific. A variety of malignant and nonmalignant conditions must be considered in the
differential diagnosis. They include [34,71]:
●Juvenile idiopathic arthritis (see appropriate topic reviews)

●Osteomyelitis (see "Hematogenous osteomyelitis in children: Clinical features and
complications")
●Epstein-Barr virus (see "Clinical manifestations and treatment of Epstein-Barr virus
infection")
●Immune thrombocytopenia (ITP) (see "Immune thrombocytopenia (ITP) in children:
Clinical features and diagnosis")
●Pertussis, parapertussis (see "Pertussis infection in infants and children: Clinical
features and diagnosis", section on 'Clinical features')
●Aplastic anemia (see "Acquired aplastic anemia in children and adolescents")
●Acute infectious lymphocytosis (see "Approach to the child with lymphocytosis or
lymphocytopenia")
●Other malignancies with bone marrow involvement (eg, neuroblastoma,
retinoblastoma, rhabdomyosarcoma, and Ewing sarcoma) (see appropriate topic
reviews)
●Hypereosinophilic syndrome (see "Hypereosinophilic syndromes: Clinical
manifestations, pathophysiology, and diagnosis")
RISK GROUP STRATIFICATION/CLASSIFICATION — Current treatment protocols for

ALL in children emphasize risk-based therapy in order to reduce toxicity in low-risk patients
while ensuring appropriate, more aggressive therapy for those with a high risk of relapse.
Risk group stratification incorporates information regarding the tumor immunophenotype,
cytogenetic findings, patient age, white blood cell count at the time of diagnosis, and
response to initial therapy, including minimal residual disease (MRD) assessment (table 3).
This is discussed in more detail separately. (See "Risk group stratification and prognosis for
acute lymphoblastic leukemia in children and adolescents".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education

materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
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patients who want a general overview and who prefer short, easy-to-read materials. Beyond
the Basics patient education pieces are longer, more sophisticated, and more detailed.
These articles are written at the 10th to 12th grade reading level and are best for patients
who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Leukemia in children (The Basics)")
SUMMARY
●Acute lymphoblastic leukemia (ALL) is the most common form of cancer in children.
The peak incidence occurs between two and five years of age. Children with certain
genetic and immunodeficiency syndromes are at increased risk. These include Down
syndrome, neurofibromatosis type 1, Bloom syndrome, and ataxia telangiectasia.
(See 'Epidemiology' above.)
●The most common presenting symptoms of ALL are nonspecific: fever, infection,
bleeding, bone pain, or lymphadenopathy. Unexplained persistence of any of these
common signs or symptoms should prompt consideration of malignancy as a possible
cause. (See 'Early signs and symptoms' above.)
●The diagnosis and classification of leukemia are based upon specialized tests
(morphology, immunophenotype, and cytogenetics) that are performed on leukemic
lymphoblasts derived from bone marrow or tissue biopsy specimens.
(See 'Diagnosis' above.)
●Children who are suspected of having leukemia should be referred to a pediatric
cancer center for evaluation and treatment. (See 'Initial evaluation' above
and "Overview of the treatment of acute lymphoblastic leukemia in children and
adolescents".)
INTRODUCTION — In the World Health Organization classification system for hematologic

malignancies, the lymphoblastic neoplasms, which may present as
leukemia and/or lymphoma, are divided into two general categories based upon lineage
(see "Classification of the hematopoietic neoplasms") [1,2]:

lymphoblastic leukemia (precursor B cell ALL)
precursor T cell acute lymphoblastic leukemia (precursor T cell ALL)
This is largely done because the prognosis and treatment differ between neoplasms of B
and T cell lineage. These can be further divided into either lymphoblastic lymphoma or
lymphoblastic leukemia:
●Clinically, a case is defined as lymphoma (LBL) if there is a mass lesion in the

mediastinum or elsewhere and <25 percent blasts in the bone marrow.
●It is classified as leukemia (ALL) if there are >25 percent bone marrow blasts, with or
without a mass lesion.
Within each lineage group, there is significant biological and clinical overlap between
neoplasms diagnosed as LBL and ALL. Although some patients present with predominantly
lymphomatous involvement (eg, a mediastinal mass or another defined lesion), most have
or later develop marrow involvement. Similarly, patients who present with leukemia may
have or may develop extramedullary tumors. Accordingly, lymphoblastic lymphoma and
acute lymphoblastic leukemia should be considered the same disease with different clinical
presentations [3].
The pathobiology, diagnosis, and clinical presentation of precursor B

lymphoblastic leukemia/lymphoma will be discussed here. The diagnosis of precursor T
lymphoblastic leukemia/lymphoma and the treatment of these disorders are discussed
separately. (See "Induction therapy for Philadelphia chromosome negative acute
lymphoblastic leukemia in adults" and "General principles of hematopoietic cell
transplantation for acute lymphoblastic leukemia in adults".)
CELL OF ORIGIN — Precursor B-lymphoblastic leukemia/lymphoma, also called precursor

B cell acute lymphoblastic leukemia (precursor B cell ALL), is postulated to arise from
precursor B cells at varying stages of differentiation. As with other forms of acute leukemia,
in experimental systems only a small fraction of tumor cells appear to be able to establish
disease in immunodeficient mice, suggesting that the tumor is maintained by a small
number of leukemia initiating cells (so-called leukemia stem cells). Uncertainty remains
regarding the precise identity of these cells, which may lie at the root of precursor B-
ALL/LBL and therefore be the key cells to target if patients are to be cured [4].
EPIDEMIOLOGY — Precursor B-ALL/LBL accounts for approximately 2 percent of the

lymphoid neoplasms diagnosed in the United States [5]. It occurs most frequently in
childhood, but can also be seen in adults, with an overall median age in adults of 39 [6]. In
the United States, the incidence is approximately 11 cases per million persons per year [7].
Precursor B-ALL occurs slightly more frequently in males than females, and three times as
frequently in Whites as in Blacks [7]. Hispanics have the highest incidence of any ethnic
group. Incidence appears to be increased in certain areas of Central and South America
(eg, Guatemala, Peru) [8]. The bases for these variations in incidence are unknown.
CLINICAL FEATURES — Precursor B-ALL/LBL more frequently presents in its leukemic

form (precursor B cell ALL) than its lymphomatous form (precursor B cell LBL). The disease
tempo is variable with some patients presenting with symptoms progressing slowly over
weeks to months and with others presenting more acutely.
Patients with precursor B cell ALL typically present with symptoms related to anemia,
thrombocytopenia, and neutropenia due to replacement of the bone marrow with tumor.
Symptoms can include fatigue, easy or spontaneous bruising/bleeding, and infections. B-
symptoms, such as fever, night sweats, and unintentional weight loss are often present, but
may be mild. Hepatomegaly, splenomegaly, and lymphadenopathy can be seen in up to half
of adults on presentation. Central nervous system (CNS) involvement is common and can
be accompanied by cranial neuropathies or symptoms, predominantly meningeal, related to
increased intracranial pressure.
By definition, patients with precursor B cell LBL present with a mass lesion and have <25
percent blasts in the bone marrow. Unlike precursor T cell LBL, mediastinal masses are
rare but lymph nodes and extranodal sites, such as the bone and the skin, are more
frequently involved [9]. A study of 53 children with B cell LBL enrolled on three prospective
trials reported the following areas as the main location of disease at the time of diagnosis
[10]: osteolytic bone lesions (26 percent), skin or subcutaneous lesions (23 percent),
mediastinal or pleural disease (11 percent), bone marrow (13 percent), lymph nodes alone
(13 percent), gonads (6 percent), head and neck (4 percent), or kidney and digestive
system (2 percent each). Upon further evaluation, 43 percent had bone marrow involvement
and 6 percent had CNS involvement at diagnosis.
PATHOLOGIC FEATURES
Morphology — On peripheral blood smears, lymphoblasts vary from small cells with scant
cytoplasm, condensed nuclear chromatin, and indistinct nucleoli to larger cells with
moderate amounts of cytoplasm, dispersed chromatin, and multiple nucleoli (picture 1). A
few azurophilic cytoplasmic granules may be present. Auer rods are absent.
oval, or convoluted nuclei, fine chromatin and indistinct or small nucleoli (picture
2 and picture 3). Occasional cases have larger cells. Precursor B LBL/ALL is
morphologically indistinguishable from precursor T ALL/LBL.
Histochemistry and immunophenotype — Evaluation often includes both histochemistry

and flow cytometry, the latter being more informative. On histochemistry, the blasts often
show "chunky" positivity on periodic acid Schiff (PAS) staining, variable positivity for
nonspecific esterase and sudan black B, and universal negativity for myeloperoxidase.
Of greater importance is characterization with antibody stains, which are usually carried out
by flow cytometry (figure 1). The blasts are virtually always positive for terminal
deoxytransferase (TdT) (picture 4) and variably express the B cell markers CD19, CD22,
CD20 and CD79a, leukocyte common antigen CD45 and common acute lymphoblastic
leukemia antigen CD10 (CALLA). T cell markers such as CD3 are negative.
The constellation of antigens identified defines the stage of differentiation, ranging from
(earliest to latest):
●Early precursor B (pro-B-ALL) – membrane CD19+, CD79a+, and cytoplasmic CD22+
●Common ALL – CD10+
●Late pre-B ALL – CD20+, cytoplasmic mu heavy chain
Approximately 40 percent of cases will express the lineage-independent stem cell antigen
CD34.
Co-expression of myeloid antigens is seen in up to 30 percent of cases, most commonly

CD13 (14 percent) and/or CD33 (16 percent) [11,12]. Expression of CD13 and CD33 is
associated with the presence of rearrangements involving the ETV6 gene (previously called
TEL), usually as part of a t(12;21)(p12;q22) that creates an ETV6-CBFA2 (or TEL-AML1)
fusion gene. Co-expression of CD68, CD15, and CD33 is often seen in cases with
rearrangements involving the MLL gene, such as t(4;11) [12]. (See "Cytogenetics and
molecular genetics in acute lymphoblastic leukemia" and 'Genetic features' below.)
Genetic features — Rearrangement of antigen receptor genes is variable in lymphoblastic

neoplasms, and may not be lineage-specific; thus, precursor B cell neoplasms may have
either or both immunoglobulin heavy chain and T cell receptor gamma or beta chain gene
rearrangements, or may lack rearrangements [13-15]. As such, we rely upon an analysis of
immunophenotype to designate T cell or B cell lineage.
Chromosomal abnormalities are common in precursor-B lymphoblastic neoplasms.

Although not specifically used in the diagnosis of precursor B cell LBL/ALL, they are
important for prognosis. They are typically divided into numerical changes and
translocations. Also important are certain point mutations. These are discussed in the
following sections.
Numerical changes — Numerical changes in chromosomes include the following:
●Hyperdiploidy >50 chromosomes

●Hypodiploidy <45 chromosomes
●Pseudodiploidy/translocations
The frequency of these abnormalities varies between children and adults, and some are
associated with characteristic immunophenotypes and/or clinical behavior.
Hyperdiploidy (51 to 65 chromosomes; DNA index 1.16-1.6) is seen in up to 50 percent of

cases of childhood precursor B-ALL and is associated with a good prognosis, particularly
those with trisomies of chromosomes 4, 10, 17 and 18. This is due in part because of its
association with the t(12;21), which is the most common translocation in childhood B-ALL.
Both abnormalities are much less common in adult ALL.
Hypodiploidy (less than 45 chromosomes) is uncommon, occurring in around 1 percent of
B-ALL in children and adolescents, and is associated with poor event-free survival and
overall outcome [16].
Translocations — Many different translocations have been reported in B-ALL, three of

which are clearly associated with treatment failure or success when using intensive
chemotherapy. These include:
●The Philadelphia chromosome: t(9;22)(q34;q11); BCR/ABL1: historically associated

with a poor prognosis, this is the most frequent rearrangement in adult ALL. It is
present in 25 percent of adult and 3 percent of childhood cases. The incidence of
t(9;22) increases with age and is present in 40 to 50 percent of patients older than 60
years. A high fraction of Philadelphia chromosome positive B-ALLs are associated with
loss of function mutations in Ikaros (encoded by the IKZF1) [17], a transcriptional
repressor that regulates lymphoid development. Outcomes in BCR/ABL1+ B-ALL has
improved significantly with the addition of ABL tyrosine kinase inhibitors to therapeutic
regimens [18]. Of interest, a subset of B-ALL with Ikaros mutations that lacks the
Philadelphia chromosome has also been described; these continue to be associated
with a very poor prognosis [19]. (See "Cytogenetics and molecular genetics in acute
lymphoblastic leukemia", section on '4;11 translocation'.)
●t(v;11q23); KMT2A (formerly known as MLL) rearranged: associated with a poor
prognosis, seen in infants <1 year and adults [20].
●t(12;21)(p12;q22) ETV6-RUNX1 (formerly known as TEL/AML1): associated with a
good prognosis and hyperdiploidy, this is the most common rearrangement seen in
children [21].
The t(9;22) and t(v;11q23) are often associated with a pro-B immunophenotype and a poor
prognosis [11,20], while the t(12;21) is associated with common pre-B ALL. Reports have
also described a cryptic t(X;14) involving the IgH locus and the cytokine receptor
gene CRLF2 that is also associated with IKZF1 mutations and a poor outcome [22]. A more
detailed discussion of chromosomal abnormalities in ALL is presented separately.
(See "Cytogenetics and molecular genetics in acute lymphoblastic leukemia".)
Point mutations and small indels — As already mentioned, mutations that disrupt IKZF1,
which encodes the transcription factor Ikaros, are associated with poor outcomes [19].
These generally consist of small deletions that lead to production of IKZF1 splice variants
with dominant negative activity. Mutations that disrupt TP53 are found in 10 to 15 percent of
B-ALL and are associated with hypodiploidy and a dismal prognosis, particularly if they are
associated with deletion of the other TP53 allele on chromosome 17q [23,24].
Gene expression — Approximately 10 percent of childhood B-ALL and 25 percent of adult
B-ALL are associated with a gene expression signature resembling that seen in
Philadelphia chromosome positive B-ALL [25]. Many of these tumors are BCR-
ABL1 positive, but others have one or another of a diverse collection of gene
rearrangements that produce hyperactivity in other tyrosine kinases (eg, the erythropoietin
receptor or JAK kinases) or cytokine signaling proteins (eg, CRLF2). Like the presence
of BCR-ABL1 fusion genes, this signature is associated with a poor outcome, but many of
the underlying signaling abnormalities are potentially targetable with kinase inhibitors.
Clinical trials are being designed to test the efficacy of such targeted therapeutics.
(See "Cytogenetics and molecular genetics in acute lymphoblastic leukemia", section on
'BCR-ABL1-like B cell ALL'.)
DIAGNOSIS — The diagnosis of precursor B-lymphoblastic leukemia/lymphoma is made

based upon the results of a bone marrow aspirate with or without biopsy, and aspirate with
or without biopsy of other involved tissues, such as lymph nodes or skin. In addition to
histological analysis, portions of the aspirated material should be sent for flow cytometry
and cytogenetic evaluation.
It is essential to find blasts in the peripheral blood, bone marrow, or tissue biopsy. Their
morphology varies, but is identical in precursor B LBL/ALL and precursor T ALL/LBL. In
some instances, the blasts are so undifferentiated that morphologic distinction from acute
myeloid leukemia (AML) is difficult or impossible. Because antigen receptor gene
rearrangements are not entirely lineage specific, immunophenotype plays a key role in the
diagnosis of precursor B LBL/ALL.
Precursor B cell LBL/ALL (like precursor T cell LBL/ALL) is distinguished from AML by its
positivity for TdT and lack of staining for myeloperoxidase. The B cell lineage is then
identified by expression of B cell antigens (eg, CD19, CD22, CD20 and CD79a) and lack of
expression of T cell antigens (eg, CD3). In more primitive precursor B cell LBL/ALLs, CD19
may be the only B lineage marker present, whereas more mature tumors tend to express
CD20. Surface immunoglobulin, the hallmark of a mature B cell, is absent, but cytoplasmic
Ig mu heavy chain may be detected in more mature tumors.
The term precursor B cell acute lymphoblastic leukemia (B-ALL) is used if there are >25
percent bone marrow blasts, with or without a mass lesion. For cases with a mass lesion
and less than 25 percent bone marrow involvement, the term precursor B cell lymphoblastic
lymphoma (B-LBL) is used.
DIFFERENTIAL DIAGNOSIS — Precursor B cell LBL/ALL must be differentiated from other

forms of lymphoma and leukemia and from the presence of increased numbers of normal
maturing B cell precursors, known as hematogones. Most notably, precursor B
cell LBL/ALL is differentiated from precursor T cell LBL/ALL by immunophenotypic analysis,
which demonstrates B cell antigens and the absence of T cell antigens. In addition,
precursor B and T cell LBL/ALL are differentiated from AML by their positivity for TdT and
lack of staining for myeloperoxidase. Although hematogones may be suggested by findings
on immunohistochemical staining of bone marrow biopsy specimens [26], they can be most
easily distinguished from precursor B cell LBL/ALL by multicolor flow cytometry [27].
(See "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute
lymphoblastic leukemia/lymphoma" and "Clinical manifestations, pathologic features, and
diagnosis of acute myeloid leukemia".)
PROGNOSIS — Both tumor and patient characteristics can be used to predict treatment
outcomes in precursor B cell ALL/LBL. In particular, age at diagnosis
and cytogenetic/genetic findings appear to be the strongest predictors of survival. As
examples:
●The outcome is less favorable in infants less than one year of age and in adults and
more favorable in children.
●In infants, many cases have translocations involving the KMT2A (MLL) gene at
11q23, which is associated with a poor prognosis at any age [20].
●Adult precursor B-ALL is more often associated with the poor-prognosis t(9;22) or
t(v11q23) abnormalities, and survival is poorer than in childhood cases [11,28]. Other
poor prognostic factors include hypodiploidy, IKZF1 mutations, and an expression
signature resembling that associated with t(9;22)-positive cases. (See "Cytogenetics
and molecular genetics in acute lymphoblastic leukemia", section on 'BCR-ABL1-like B
cell ALL'.)
●Older children more often have hyperdiploidy and the t(12;21), which confer a better
prognosis (85 to 90 percent long-term survival) [21].
●Myeloid antigen expression does not seem to be an independent prognostic factor in
ALL [12,29]. Overall, the prognosis for these patients may be worse than that for adults
with T cell LBL/ALL.
While not yet routine, all acute leukemias seen at our institution are subjected to analysis
using a targeted next-generation sequencing platform that covers certain genes that are
prognostically important, such as IKZF1 and TP53.
The relationship between prognosis and cytogenetic abnormalities in ALL is discussed in

more detail elsewhere. (See 'Genetic features' above and "Cytogenetics and molecular
genetics in acute lymphoblastic leukemia".)
●Basics topics (see "Patient education: Acute lymphoblastic leukemia (ALL) (The
Basics)")
●Beyond the Basics topics (see "Patient education: Acute lymphoblastic leukemia
(ALL) treatment in adults (Beyond the Basics)")
SUMMARY
●Precursor B-lymphoblastic leukemia/lymphoma, also called precursor B cell acute

lymphoblastic leukemia (precursor B cell ALL) is postulated to arise from precursor B
cells at varying stages of differentiation.
●The term precursor B cell acute lymphoblastic leukemia (B-ALL) is used if there are
>25 percent bone marrow blasts, with or without a mass lesion. For cases with a mass
lesion and less than 25 percent bone marrow involvement, the term precursor B cell
lymphoblastic lymphoma (B-LBL) is used. (See 'Introduction' above and "Clinical
manifestations, pathologic features, and diagnosis of precursor T cell acute
lymphoblastic leukemia/lymphoma", section on 'Introduction'.)
●Precursor B-ALL/LBL, which accounts for approximately 2 percent of the lymphoid
neoplasms, occurs most frequently in childhood, but can also be seen in adults.
(See 'Epidemiology' above.)
●Peripheral blood smear, bone marrow biopsy, and tissue biopsy can demonstrate
lymphoblasts with varying morphology. Precursor B LBL/ALL is morphologically
indistinguishable from precursor T ALL/LBL. (See 'Morphology' above.)
●Key diagnostic studies include histochemical stains, immunocytochemistry, and flow
cytometry. These are required to differentiate between precursor B-
ALL/LBL, precursor T-ALL/LBL, and other acute leukemias. (See 'Histochemistry and
immunophenotype' above.)
●Although not specifically used in the diagnosis of precursor B
cell LBL/ALL, cytogenetic analysis is of prognostic importance in B lineage tumors.
Some centers screen for IKZF1 mutations, which confer a poor prognosis. Tests are
under development that will permit identification of tumors with gene expression
signatures that confer a worse prognosis. (See 'Genetic features' above
and "Cytogenetics and molecular genetics in acute lymphoblastic leukemia".)
●The diagnosis of precursor B-lymphoblastic leukemia/lymphoma is made based upon
the results of a bone marrow biopsy with or without biopsy of other involved tissues,
such as lymph nodes or skin. (See 'Diagnosis' above.)
●Both tumor and patient characteristics can be used to predict treatment outcomes in
precursor B cell ALL/LBL. In particular, age at diagnosis and chromosomal changes
appear to be the strongest predictors of survival. (See 'Prognosis' above.)
INTRODUCTION — In the World Health Organization classification system for hematologic

malignancies, the lymphoblastic neoplasms, which may present as
leukemia and/or lymphoma, are divided into two general categories based upon lineage
(see "Classification of the hematopoietic neoplasms") [1,2]:

lymphoblastic leukemia (precursor B cell ALL)
precursor T cell acute lymphoblastic leukemia (precursor T cell ALL)
This is largely done because the prognosis and treatment differ between neoplasms of B
and T cell lineage. These can be further divided into either lymphoblastic lymphoma or
lymphoblastic leukemia:
●Clinically, a case is defined as lymphoma (LBL) if there is a mass lesion in the

mediastinum or elsewhere and <25 percent blasts in the bone marrow.
●It is classified as leukemia (ALL) if there are >25 percent bone marrow blasts, with or
without a mass lesion.
Within each lineage group, there is significant biological and clinical overlap between
neoplasms diagnosed as LBL and ALL. Although some patients present with predominantly
lymphomatous involvement (eg, a mediastinal mass or another defined lesion), most have
or later develop marrow involvement. Similarly, patients who present with leukemia may
have or develop extramedullary tumors. Accordingly, lymphoblastic lymphoma and acute
lymphoblastic leukemia should be considered the same disease with different clinical
presentations [3].
The pathobiology, diagnosis, and clinical presentation of precursor T
lymphoblastic leukemia/lymphoma will be discussed here. The diagnosis of precursor B cell
lymphoblastic leukemia/lymphoma and the treatment of these disorders are discussed
separately. (See "Induction therapy for Philadelphia chromosome negative acute
lymphoblastic leukemia in adults" and "General principles of hematopoietic cell
transplantation for acute lymphoblastic leukemia in adults".)
CELL OF ORIGIN — Precursor T-lymphoblastic leukemia/lymphoma (precursor T-LBL),

also called precursor T cell acute lymphoblastic leukemia (precursor T cell ALL) is
postulated to arise from precursor T lymphoblasts at varying stages of differentiation. As
with other forms of acute leukemia, in experimental systems only a small fraction of tumor
cells appear to be able to establish disease in immunodeficient mice, suggesting that the
tumor is maintained by a small number of leukemia initiating cells (so-called leukemia stem
cells). Uncertainty remains regarding the precise identity of these cells, which may lie at the
root of T-LBL and therefore be the key cells to target if patients are to be cured [4].
EPIDEMIOLOGIC DATA — Precursor T cell LBL/ALL occurs most frequently in late

childhood, adolescence, and young adulthood, with a 2:1 male predominance; it comprises
15 and 25 percent of childhood and adult ALL, respectively, and 2 percent of adult non-
Hodgkin lymphoma [3,5-7]. The incidence in the United States is approximately three cases
per million persons per year and does not vary by ethnicity [7].
CLINICAL PRESENTATION — Patients are usually males in their teens to early twenties
who present with lymphadenopathy in cervical, supraclavicular, and axillary regions (50
percent), or with a mediastinal mass (50 to 75 percent) [8,9]. In most patients the
mediastinal mass is anterior, bulky, and associated with pleural effusions. These masses
can produce such complications as superior vena cava syndrome, tracheal obstruction, and
pericardial effusions (with or without tamponade). The disease tempo is variable with some
patients presenting with symptoms progressing slowly over weeks to months and with
others presenting more acutely. (See "Malignancy-related superior vena cava syndrome".)
Less commonly, patients present with extranodal disease (eg, skin, testicular, or bony
involvement). Abdominal involvement is very unusual, but when it does occur it is found
primarily in the liver and spleen.
More than 80 percent of patients present with stage III or stage IV disease and almost 50
percent have B symptoms; in the majority, serum lactate dehydrogenase (LDH) levels are
elevated. Although the bone marrow is frequently normal at presentation, approximately 60
percent of patients develop bone marrow infiltration and a subsequent leukemic phase
indistinguishable from T cell ALL [10].
Evaluation of the spinal fluid is essential to rule out central nervous system (CNS)
involvement, which is frequently seen. Patients with bone marrow involvement have a
particularly high incidence of CNS infiltration. Parenchymal involvement of the brain may
occur in both T-ALL and B-ALL, but is much less common.
PATHOLOGIC FEATURES
Morphology — On peripheral blood smears, lymphoblasts vary from small cells with scant
cytoplasm, condensed nuclear chromatin, and indistinct nucleoli to larger cells with
moderate amounts of cytoplasm, dispersed chromatin, and multiple nucleoli. A few
azurophilic cytoplasmic granules may be present. Auer rods are never seen.
oval, or convoluted nuclei, fine chromatin and indistinct or small nucleoli (picture
1 and picture 2 and picture 3). Occasional cases have larger cells. Precursor T
cell LBL/ALL is morphologically indistinguishable from precursor B cell ALL/LBL.
Immunophenotype and histochemistry — As in precursor B cell LBL/ALL, evaluation

often includes both histochemistry and flow cytometry. On histochemistry, the blasts often
show "chunky" positivity on periodic acid Schiff (PAS) staining, variable positivity for
nonspecific esterase and Sudan black B, and negativity for myeloperoxidase.
On flow cytometry, the lymphoblasts are typically positive for CD7 and either surface or
cytoplasmic CD3, and variably express CD2, CD5, CD1a, CD4 and/or CD8 (figure 1). A
subset of tumors is positive for CALLA (CD10). Only surface CD3 is entirely lineage-
specific, and a panel of markers should be used to confirm the diagnosis. The stage of T
cell differentiation can then be determined by evaluation of a constellation of antigens
(earliest to latest) [1]:
●Early or pro-T - CD2, CD5, CD7, CD38 and cytoplasmic CD3 (30 percent)
●Common thymocyte - CD1a, sCD3, CD4/CD8 double positive (50 percent)
●Late thymocyte - CD4 or CD8 single positive (20 percent)
There is some correlation with presentation and differentiation stage (cases with bone
marrow and blood presentation in general are arrested at earlier differentiation stage than
cases with thymic presentation [11,12]); however, there is significant overlap [13]. In one
report in children, no relationship was found between clinical outcome and maturational
stage [14], while in an adult study, the complete remission rate was significantly higher in
those with the more mature T cell variants (91 versus 56 percent) [15].
Approximately half of T cell LBLs express the homing receptor/cell adhesion molecule
CD44. Expression of CD44 correlates with maturation, as CD4-/CD8- tumors are CD44+
whereas CD4+/CD8+ tumors tend to be CD44-. CD10, on the other hand, correlates with
lymphomatous presentation, as approximately 40 percent of T cell LBLs express CD10; by
comparison, less than 10 percent of T cell ALLs are CD10+.
Rare cases of LBL express antigens present on NK cells (CD16, CD57).
Genetic features — Rearrangement of antigen receptor genes is variable in lymphoblastic

neoplasms, and may not be lineage-specific; thus, precursor T cell neoplasms may have
either or both T cell receptor (TCR) beta or gamma chain gene rearrangements and
immunoglobulin heavy chain gene rearrangements [16]. As such, immunophenotyping is
used to determine T cell or B cell lineage.
Chromosomal translocations involving the TCR alpha and delta loci at chromosome 14q11
and beta and gamma loci at 7q34 are present in about one-third of the cases [17,18]; the
partner genes are variable and include the transcription
factors MYC (8q24), TAL1/SCL (1p32), LMO1 (11p15), LMO2 (11p13), and HOX11 (10q24)
and the cytoplasmic tyrosine kinase LCK (1p34). In an additional 25 percent,
the TAL1 locus at 1p32 has deletions in the 5' regulatory region [19]; together with
translocations, rearrangements of TAL1 are the most common chromosomal aberration
involving a proto-oncogene in T-ALL. Deletions of 9p involving deletion of INK4, the p16
(INK4a) tumor suppressor gene (CDK4 inhibitor), are also seen in a high fraction of T-
lymphoblastic neoplasms.
A rare t(7;9)(7q34;9q34.3) involving the NOTCH1 gene is found in less than 1 percent of T-
ALLs. Much more common are point mutations involving NOTCH1, which result in
excessive activation of the NOTCH1 receptor. NOTCH1 is the most commonly mutated
oncoprotein in T-ALL [20]. Recognition of NOTCH1 mutations has led to attempts to treat
refractory T-ALL with NOTCH pathway inhibitors [21], which are still being tested in ongoing
clinical trials.
One report found that 61 percent of pediatric patients had an abnormal karyotype, the most
common abnormalities being del(6q) and 14q11 breakpoints. Other abnormalities included
del(9p), trisomy 8, 11q23 breakpoints, 14q32 translocations, and 7q32-q36 breakpoints. In
contrast to precursor B cell lymphoblastic leukemia/lymphoma, cytogenetics are not of
prognostic significance in the patients with T cell ALL/LBL.
We subject all acute leukemias to targeted DNA sequencing using a next generation
sequencing platform. In addition to frequent mutations in NOTCH1 and less common
mutations in FBXW7 (a negative regulator of MYC and NOTCH1) and PTEN, we have
found that mutations in TP53 are seen in 10 to 15 percent of patients, and are more
common in relapsed/refractory disease than de novo disease.
A more detailed discussion of chromosomal abnormalities in ALL is presented separately.

(See "Cytogenetics and molecular genetics in acute lymphoblastic leukemia".)
DIAGNOSIS — The diagnosis of precursor T-lymphoblastic leukemia/lymphoma is made

based upon the results of a bone marrow aspirate, and/or biopsy, and/or aspirate with or
without biopsy of other involved tissues, such as the mediastinum. In addition to histological
analysis, portions of the aspirated material or biopsy specimen should be sent for flow
cytometry and cytogenetic evaluation (which should now be considered standard in all
acute leukemias).
Lymphoblasts are present in the peripheral blood, bone marrow, or tissue biopsy. Their
morphology varies, but is identical in precursor T LBL/ALL and precursor B ALL/LBL. In
some instances, the blasts are so primitive that morphologic distinction from acute myeloid
leukemia (AML) is difficult or impossible. Because antigen receptor gene rearrangements
are not lineage specific, immunophenotype plays a key role in the diagnosis of precursor
T LBL/ALL.
The blasts can be distinguished from the myeloblasts of acute myeloid leukemia (AML) by
their positivity for TdT (picture 4) and lack of staining for myeloperoxidase. The T cell
lineage is then identified by evaluation of a panel of T cell antigens, including CD3.
The term precursor T cell acute lymphoblastic leukemia (T-ALL) is used if there are >25
percent bone marrow blasts, with or without a mass lesion. For cases with a mass lesion
and less than 25 percent bone marrow involvement, the term precursor T cell lymphoblastic
lymphoma (T-LBL) is used.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis for precursor T

cell LBL/ALL includes other forms of lymphoma and leukemia. Most notably, precursor T
cell LBL/ALL is differentiated from precursor B cell LBL/ALL by immunophenotypic analysis,
which demonstrates the presence of T cell antigens and the absence of B cell antigens. In
addition, precursor T and B cell LBL/ALL are differentiated from AML by their positivity for
TdT and lack of staining for myeloperoxidase. (See "Clinical manifestations, pathologic
features, and diagnosis of precursor B cell acute lymphoblastic
leukemia/lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of
acute myeloid leukemia".)
Indolent T-lymphoblastic proliferation is a nonmalignant entity that may mimic precursor T

LBL histologically but is clinically indolent [2,22]. Most cases demonstrate infiltration of
lymphoid tissue of the upper aerodigestive tract. Although infiltrating blasts are TdT positive,
the cells are not clonal and have a developmentally normal, nonaberrant phenotype.
PROGNOSTIC FACTORS — Prior to the development of aggressive ALL-type therapy, this

disease was rapidly fatal. Currently, children with T-ALL treated with such therapeutic
regimens have outcomes similar to those of children with B-ALL. Treatment of precursor T-
ALL is generally more aggressive than that for precursor B-ALL, and is the same for
lymphomatous and leukemic presentations [23]. Among adults, T-ALL has a more favorable
outcome than B-lineage ALL. This may be related to younger patient age and lack of
distinctive adverse cytogenetic abnormalities. (See "Overview of the treatment of acute
lymphoblastic leukemia in children and adolescents".)
Gene expression profiling and other studies have identified a number of genes associated
with response to induction therapy and remission duration in T cell ALL [24]. The profiles in
adults [25] and children [26] show some divergence, which might explain differences in
outcomes of adults and children. On the other hand, adult chemotherapy regimens have not
been as intensive as those used in children, and it remains possible that differences in
therapy in adult and childhood T-ALL (as well as B-ALL) may at least in part explain worse
outcomes in adults.
Prognostic factors for T cell ALL were evaluated in 356 adult patients treated uniformly on
the prospective trial UKALL XII/ECOG 2993, in which complete remission was observed in
94 percent and five-year overall survival was 48 percent. The following prognostic variables
were described [27]:
●Survival was significantly shorter for females than males (41 versus 50 percent) and
for those >35 years of age (38 versus 52 percent).
●Positivity of blasts for CD1a and lack of expression of CD13 were associated with
significantly better survival. Complex cytogenetic abnormalities were associated with a
significantly poorer five-year survival (19 versus 51 percent).
●Patients with a matched sibling donor had significantly better five-year survival than
those without such donors (61 versus 46 percent).
●The outcome following relapse was dismal, with only 8 of the 123 (6.5 percent)
relapsed patients surviving at a median of 5.2 years. Six of the eight survivors had
undergone allogeneic transplantation.
In another study of 212 adults with T cell ALL enrolled on prospective trials, analysis for
mutations in NOTCH1 and/or FBXW7 (N/F), K-RAS, and PTEN was able to classify patients
into prognostically "low-risk" and "high-risk" groups [28]. Approximately half of cases had a
"low-risk" profile consisting of N/F mutations without K-RAS or PTEN mutations. When
compared with all other patients, "low-risk" disease was associated with significantly longer
event-free survival (hazard ratio [HR] 3.2; 95% CI 1.9-5.15) and overall survival (HR 3.2;
95% CI 1.9-5.6). Minimal residual disease testing post-treatment at various time points is
now considered standard in the follow-up and management of both B- and T-ALL and has
been shown to be prognostic.
It also is increasingly appreciated that mutations in TP53 are found in 10 to 15 percent of T-

ALL, are particularly common in relapsed/refractory disease, and are associated with a
dismal prognosis, particularly if they are associated with deletion of the other TP53 allele on
chromosome 17q [29].
It is clear from these observations that disease relapse is a more common cause of death
than failure to achieve complete remission. The pros and cons of hematopoietic cell
transplantation for preventing relapse in ALL are discussed separately. (See "General
principles of hematopoietic cell transplantation for acute lymphoblastic leukemia in adults".)

●Basics topics (see "Patient education: Acute lymphoblastic leukemia (ALL) (The
Basics)")
●Beyond the Basics (see "Patient education: Acute lymphoblastic leukemia (ALL)
treatment in adults (Beyond the Basics)")
SUMMARY
●Precursor T-lymphoblastic leukemia/lymphoma (precursor T-LBL), also called

precursor T cell acute lymphoblastic leukemia (precursor T cell ALL) is postulated to
arise from precursor T lymphoblasts at varying stages of differentiation.
●The term precursor T cell acute lymphoblastic leukemia (T-ALL) is used if there are
>25 percent bone marrow blasts, with or without a mass lesion. For cases with a mass
lesion and less than 25 percent bone marrow involvement, the term precursor T cell
lymphoblastic lymphoma (T-LBL) is used. (See 'Introduction' above.)
●Precursor T cell LBL/ALL occurs most frequently in late childhood, adolescence, and
young adulthood, with a male predominance; it comprises 15 percent of childhood and
25 percent of adult ALL and 2 percent of adult non-Hodgkin lymphoma.
(See 'Epidemiologic data' above.)
●Peripheral blood smear, bone marrow biopsy, and tissue biopsy can demonstrate
lymphoblasts with varying morphology. Precursor T LBL/ALL is morphologically
indistinguishable from precursor B ALL/LBL. (See 'Morphology' above.)
●Key diagnostic studies include histochemical stains, immunocytochemistry, and flow
cytometry. These are required to differentiate among precursor T-
ALL/LBL, precursor B-ALL/LBL, and other acute leukemias. (See 'Immunophenotype
and histochemistry' above.)
●A number of genetic abnormalities have been identified in patients with precursor T-
ALL/LBL, but at present these are not prognostically important. (See 'Genetic
features' above and "Cytogenetics and molecular genetics in acute lymphoblastic
leukemia".)
●The diagnosis of precursor T-lymphoblastic leukemia/lymphoma is made based upon
the results of a bone marrow biopsy with or without biopsy of other involved tissues,
such as the mediastinum. (See 'Diagnosis' above.)
●Age at diagnosis and chromosomal abnormalities appear to be important prognostic
factors. (See 'Prognostic factors' above.)
●While not yet routine, all acute leukemias seen at our institution are subjected to analysis
using a targeted next-generation sequencing platform that covers certain genes that are
prognostically important in T-ALL/LBL, such as TP53.
INTRODUCTION — The most useful prognostic indicators in acute lymphoblastic leukemia

(ALL) are age, white blood cell count, immunophenotype, minimal residual disease
detection, and karyotype. A number of recurring cytogenetic abnormalities are associated
with distinct immunologic phenotypes of ALL and characteristic outcomes [1-5]. These
abnormalities will be reviewed here. An overview of cytogenetic analysis in hematologic
malignancies, including definitions, methods of detection, and the genetic consequences of
chromosomal translocations, is presented separately, as is the use of minimal residual
disease assessment in patients with ALL. (See "General aspects of cytogenetic analysis in
hematologic malignancies" and "Detection of minimal residual disease in acute
lymphoblastic leukemia" and "Clinical use of minimal residual disease detection in acute
lymphoblastic leukemia".)
B CELL ACUTE LYMPHOBLASTIC LEUKEMIA
Cytogenetic abnormalities — Cytogenetic analysis and molecular cytogenetic studies,

such as fluorescence in situ hybridization (FISH), reveal recurring chromosome
abnormalities in approximately 80 percent of ALL, including numerical and structural
changes, such as translocations, inversions, or deletions [1,2,6-8]. These cytogenetic
abnormalities are incorporated in the World Health Organization (WHO) classification of
acute leukemia (table 1) [5].
There are substantial differences between children and adults with ALL in the frequencies of
some recurring abnormalities, including the following:
●The t(9;22) is observed in about 2 to 5 percent of children [9-11] compared with about
30 percent of adults [6,8,12].
●The t(12;21), which is detectable only by FISH or polymerase chain reaction (PCR)
analysis, is observed in about 25 percent of children with B-lineage leukemia [7,13],
compared with about 3 percent of adults.
●A hyperdiploid karyotype is found in 30 to 40 percent of children compared with 2 to
10 percent of adults [7,11].
●The t(4;11) is present in up to 60 percent of infants younger than 12 months, but is
rarely observed in adult ALL patients [7,14].
While less well understood, ALL that develops in adolescents and young adults (AYA, ages
16 to 21 years) appears to have a biology and prognosis distinct from that of younger
children and older adults [15,16]. While the best age cutoff to define this population is not
known, some clinical trials define AYA up to age 39 years. AYA appear to have a better
prognosis when treated with pediatric regimens. This is discussed in more detail separately.
(See "Induction therapy for Philadelphia chromosome negative acute lymphoblastic
leukemia in adults", section on 'Young adults/adolescents'.)
As will be described below, certain translocations, such as t(4;11) and t(9;22), are
associated with treatment failure even when using intensive chemotherapy; in comparison,
the t(12;21), t(1;19), and hyperdiploidy (50 to 60 chromosomes) are associated with a more
favorable outcome [7,9,10,12-14,17,18].
12;21 translocation in precursor B ALL — A t(12;21)(p13.2;q22.1) is the most common

genetic lesion in childhood ALL, occurring in 15 to 25 percent of children with B-lineage
disease, specifically precursor B ALL [19-22]. Most affected children are between the ages
of 1 and 10 [19,22,23]. This translocation is less common in adults, accounting for about 3
to 4 percent of patients with ALL [23,24], and is not seen in T cell ALL.
The t(12;21) is not easily detected by cytogenetic analysis because of the similarity in size
and banding patterns of 12p and 21q [19]. As a result, RT-PCR or FISH analysis is required
to detect this rearrangement [20]. (See "General aspects of cytogenetic analysis in
hematologic malignancies".)
The t(12;21) fuses the ETV6 (TEL) gene at 12p13.2 with the RUNX1/AML1 gene at
21q22.1, resulting in the production of a fusion protein [25].
●The RUNX1 protein (also known as core binding factor alpha-2, CBFA2) is a member
of a family of transcription factors with homology to the pair-rule Drosophila gene, runt.
RUNX1 heterodimerizes with another protein, core binding factor beta (CBFB, also
known as PEBP2 beta), to form a transcription factor.
●The ETV6 protein functions as a transcriptional repressor [26]. It contains two
domains: a helix-loop-helix (HLH) protein dimerization domain and an ETS DNA
binding domain.
The t(12;21) results in fusion of the 5' HLH domain of ETV6 with the 3' DNA-binding and
transactivation domain of RUNX1 [25]. ETV6-RUNX1 inhibits transactivation of gene
expression by the normal RUNX1 protein, an effect that requires the HLH domain of ETV6.
In many patients with ALL and the t(12;21), the ETV6 allele on the other chromosome 12
homolog is deleted [27], which has no effect on the favorable prognostic significance.
Alterations of both ETV6 alleles in leukemic cells suggest that ETV6 may be a tumor
suppressor gene.
The ETV6 gene is also involved in several other recurring translocations in the leukemias
and myeloproliferative disorders, including the t(5;12)(q32;p13.2) in chronic myelomonocytic
leukemia. In this translocation, ETV6 is fused to the platelet-derived growth factor receptor
(PDGFR)-beta gene [28]. Direct evidence supporting a pathogenetic role for this fusion
protein comes from a transgenic mouse model in which expression of the ETV6-
PDGFRB fusion mRNA produces a myeloproliferative disorder that shares features with
chronic myelomonocytic leukemia [29].
The ETV6-RUNX1 fusion gene can be detected in B lineage progenitor cells during normal
prenatal hematopoiesis in approximately 1 percent of developing fetuses, but only
progresses to frank ALL in 1 percent of these cases [30]. ETV6-RUNX1 appears to induce a
preleukemic stage, but additional cooperating genetic mutations are required for the
conversion into acute leukemia [30-32].
Patients with ALL and the t(12;21) generally have a favorable prognosis [4,13,19-22]. One
series, for example, evaluated 188 patients with precursor B ALL, 48 of whom (26 percent)
had a rearrangement of the ETV6 gene [21]. Patients with the ETV6 rearrangement had a
much higher five-year event-free survival than those without the rearrangement (91 versus
65 percent). In the MRC/ECOG study, the event-free and overall survival rates at five years
of 368 childhood ALL patients with the t(12;21) were 89 and 96 percent, respectively [13]. In
another report, none of 22 patients with the ETV6/RUNX1 fusion relapsed compared with
16 of 54 (30 percent) without the ETV6-RUNX1 fusion [23].
Many of these patients would fall into a high-risk group using standard risk factors. Thus,
the presence of the t(12;21) may identify patients within the "high-risk" group who would
benefit from less toxic and less intensive therapy [21]. However, within the group of children
with ALL and the t(12;21), those with the CpG island methylator phenotype (CIMP) may be
at higher risk of relapse [33].
8;14 translocation — A reciprocal translocation involving the long arms of chromosomes 8

and 14, designated t(8;14)(q24.2;q32.3), is present in a high proportion of Burkitt cell tumors
of both African and non-African origin. The same translocation occurs in patients with ALL
with FAB-L3-type leukemia cells, suggesting that Burkitt lymphoma and most B cell ALL of
the L3 type are different manifestations of the same disease. Variant translocations have
been described in some patients with Burkitt lymphoma and B cell ALL, including
t(2;8)(p12;q24.2) and t(8;22)(q24.2;q11.2). (See "Pathobiology of Burkitt lymphoma",
section on 'Chromosomal translocations'.)
In a series of 1522 adult patients with ALL, the t(8;14) and its variants were detected in 16
(1 percent) patients [11]. Eight of these patients had a mature B cell immunophenotype,
whereas the remaining cases showed a common or pre-B (CD10-positive) phenotype.
These patients had a high incidence of central nervous system involvement at diagnosis
and a poorer prognosis than any other group of patients classified by chromosomal
abnormalities. In a series of 21 adults with a t(8;14), all of whom had B cell ALL; the
complete remission rate was 62 percent, but the median event-free survival was only two
months [2].
4;11 translocation — Translocations involving 11q23.3 are observed in 5 to 7 percent of

patients with ALL [2,4,8,11]. The most common is t(4;11)(q21.3;q23.3); the
t(11;19)(q23.3;p13.3) is second in frequency. However, about 50 percent of patients with
the latter rearrangement have AML, usually acute monoblastic leukemia (AML-M5).
(See "Cytogenetics in acute myeloid leukemia".)
Patients with the t(4;11) and ALL have a number of characteristic clinical findings
[2,4,13,14,18,34-38]:
●High leukocyte counts (median 183,000 cells/microL)

●An immature (progenitor B cell) immunophenotype (CD10-, CD19+, HLA-DR+)
●B cell lineage
●Frequent co-expression of myeloid antigens (CD15+, CDw65+)
In most cases of t(4;11) acute leukemia, the blasts are lymphoid in appearance [2,4,7]. A
notable finding is that the leukemia cells in about 50 percent of patients with the t(4;11)
express myeloid enzymes, such as myeloperoxidase or nonspecific esterase (a
granulocyte-monocyte marker) [14,39]. Thus, occasional blasts appear monocytic and, in
some patients, lymphoid and monocytoid blasts occur in approximately equal proportion
[14]. These leukemic cells are generally terminal deoxynucleotidyl transferase (Tdt) positive
and usually express pan-B cell antigens; in comparison, T cell markers are absent.
The t(4;11) fuses the KMT2A (previously called mixed-lineage, leukemia [MLL]) gene on
chromosome 11 band q23.3 to the AFF1 (AF4) gene on chromosome 4 band q21.3, forming
a KMT2A-AFF1 fusion gene, which is transcribed into a chimeric mRNA [40]. Reverse
transcriptase-polymerase chain reaction (RT-PCR) techniques have been developed for this
transcript, which have been used for monitoring of residual disease in this ALL variant [40].
(See "Detection of minimal residual disease in acute lymphoblastic leukemia".)
ALL with a t(4;11) has a poor prognosis in both adults and children. Typical findings include
a remission rate of 75 percent, but a median event-free survival of only seven months in
adults [2,8,14,41], and a complete remission rate of 88 percent but a median survival of 10
months in children [4,13,34]. In a group of 35 infant ALL patients with t(4;11), the five-year
event-free survival was only 29 percent [14].
11q23.3 translocation in infants — The majority (60 to 80 percent) of infants with ALL
have translocations involving 11q23.3 [4,36-38,42,43]. These translocations involve
the KMT2A gene [37,38,42,44,45]. The KMT2A protein is a histone methyltransferase that
assembles in protein complexes that regulate gene transcription via chromatin remodeling.
Target genes of the KMT2A transcriptional regulatory complexes include the HOX genes
and the IKZF1 (IKAROS) gene, which have a critical role in development as well as
hematopoiesis [45]. IKZF1 is a DNA-binding protein that is required for normal lymphocyte
development. Mutant mice that express only dominant-negative IKZF1 isoforms develop
ALL at three to six months of age; similar isoforms have been identified in infants with ALL
and KMT2A translocations [46]. (See "Cytogenetics in acute myeloid leukemia" and 'Gene
expression' below.)
Leukemias in infants with KMT2A translocations have a characteristic and distinctive gene
expression profile, suggesting that they constitute a distinct disease entity, characterized by
a high rate of early treatment failure and a very poor outcome [37,38,47,48]. In one series,
for example, the estimated event-free survival in infants with ALL and
a KMT2A rearrangement was 19 percent at three years compared with 46 percent for
patients with germline KMT2A [37]. In another series of 1725 childhood ALL patients, the
event-free and overall survival rates at five years were 50 and 60 percent, respectively,
compared with 89 and 96 percent of patients with a t(12;21) [13]. Among infants
with KMT2A rearrangements, the t(4;11) may confer a particularly poor prognosis; as a
result, intensified therapy, including transplantation, may be preferred in these patients
[4,13,38].
9;22 translocation — The t(9;22)(q34.1;q11.2) resulting in the Philadelphia (Ph)

chromosome is observed in about 5 percent of children [9,10] compared with about 30
percent of adults overall [4,6,8,12] and 50 percent of adults with B-lineage ALL [12]. The
normal primitive stem cells, rather than committed lymphoid progenitors, appear to be the
target for leukemic transformation [49]. The fusion product of the Ph chromosome (the
BCR-ABL1 protein), which is also seen in chronic myeloid leukemia (CML), is discussed
elsewhere. (See "Molecular genetics of chronic myeloid leukemia".)
The Ph chromosome is the most frequent rearrangement in adult ALL. In one series of 141
consecutive adults with ALL, for example, 36 (26 percent) had a t(9;22); all of these
occurred among the 109 patients with precursor B ALL [50]. However, some patients have
had both B cell and myeloid markers [9,12,51]. Because of the high frequency of the BCR-
ABL1 rearrangement and its dire clinical consequences, molecular studies using RT-PCR or
FISH should be routinely performed at diagnosis when clinical suspicion is high and
cytogenetic analysis is nondiagnostic [52].
In a large series of 1522 adult ALL patients from the UK MRC and ECOG clinical trial, 267
(19 percent) patients had the t(9;22) [11]. In this study, as well as in one reported by
CALGB [53], approximately 60 to 70 percent of patients had abnormalities in addition to the
Ph chromosome; gain of a Ph chromosome, monosomy 7, +8, +X, and del(9p) are among
the commonly associated secondary abnormalities. However, the survival significance of
these secondary chromosome abnormalities is controversial [10,11,53]. Interestingly, these
abnormalities differ from those that evolve during the accelerated and blast phases of CML.
Another difference from CML is that approximately 70 percent of patients with Ph
chromosome positive ALL have a chromosomally normal cell line in the bone marrow at
diagnosis, a rare finding in untreated CML.
Molecular studies of Ph chromosome positive ALL have revealed two distinct subgroups
[54,55]:
●In approximately 30 to 50 percent of adults, the molecular rearrangement is identical

to that seen in CML. The breaks occur within the ABL1 gene and within the major bcr
region (called M-bcr) of the BCR gene, producing a chimeric gene that encodes a 210
kilodalton fusion protein. Many of these patients have persistence of metaphase cells
with the Ph chromosome after chemotherapy-induced hematologic remissions. They
also have the Ph chromosome in myeloid cells and in myeloid colonies grown in vitro,
suggesting that they represent cases of CML presenting in lymphoid blast crisis after
an unrecognized chronic phase.
●In the remaining patients, the breakpoint occurs upstream of bcr but still within
the BCR gene (called m-bcr), giving rise to smaller fusion proteins (185 to 190
kilodaltons) [56-58]. Most of these patients lack the additional cytogenetic
abnormalities typical of CML blast crisis, do not have the Ph chromosome in myeloid
cells and colonies, and become Ph chromosome negative in hematologic remission.
These observations suggest that the Ph translocation occurred in a cell that is more
restricted in its differentiation, perhaps a committed B-lymphoid progenitor.
Both the 210 and 185 kilodalton fusion proteins are involved in constitutive signaling via the
RAS pathway of signal transduction and promote leukemogenesis [59-62]. In a mouse
model, animals transplanted with cells transfected with p185 BCR-ABL1 develop tumors
more rapidly than those transplanted with p210 BCR-ABL1 [59]. This could explain why
patients with Ph chromosome positive ALL are biologically and clinically different from those
with CML even though both disorders have the same chromosomal abnormality. The
observation that patients in whom the Ph chromosome is restricted to lymphoblasts, which
is more common with the m-bcr breakpoint, have shorter survivals than those with
multilineage involvement (median 8 versus 47 months) [54,55] is compatible with the mouse
studies showing more aggressive disease with p185 BCR-ABL1.
Ph chromosome positivity is a poor prognostic sign in ALL. Early chemotherapy trials

reported no survivors at five years in adults with this abnormality [63,64]. The initial
response is better with more intensive regimens, but the likelihood of remaining in remission
is still much lower than in those without this translocation [8]. In a prospective study
conducted by the Cancer and Leukemia Group B (CALGB), patients with ALL who were Ph
chromosome positive, when compared with those who were Ph chromosome negative, had
a similar complete remission rate (71 versus 77 percent), but a shorter median duration of
remission (10 versus 18 months) and survival (11 versus 22 months) [12]. In a later review
of clinical trials from CALGB, the likelihood of remaining in remission was much lower in
patients who were Ph chromosome positive. In the MRC/ECOG clinical trial, the five-year
event-free and overall survival rates in Ph positive ALL patients were 16 and 22 percent,
respectively, in comparison with 36 and 41 percent in those without the t(9;22) [11].
Tyrosine kinase (TK) inhibitors (eg, imatinib, dasatinib, nilotinib) that target the BCR-ABL1
fusion protein have been used in combination with chemotherapy in the initial treatment of
Ph positive ALL. The addition of a TK inhibitor results in significantly higher rates of
complete remission and overall survival. This is discussed in more detail separately.
(See "Induction therapy for Philadelphia chromosome negative acute lymphoblastic
leukemia in adults" and "Induction therapy for Philadelphia chromosome negative acute
lymphoblastic leukemia in adults", section on 'Philadelphia chromosome positive ALL'.)
1;19 translocation in pre-B cell ALL — Pre-B cell ALL is a distinct subtype of ALL that
can be distinguished from null-cell and common B cell ALL by the presence of cytoplasmic
immunoglobulin mu-chain (Cmu) expression. The pre-B leukemias have rearrangements of
the immunoglobulin heavy chain genes and occasionally of the light chain genes. The
t(1;19) occurs in approximately 30 percent of patients with pre-B cell childhood ALL [65].
Although most common in pre-B cell ALL, the t(1;19) can also occur in other B lineage cells,
including null cell and mature B cell ALL [50,65].
Children with pre-B ALL and this translocation tend to have a white blood cell count
of >20,000/microL and a characteristic surface antigen profile that is CD19+, CD10+
(CALLA+), CD22+, CD34-, and CD20+/- [66,67]. In comparison, the t(1;19) is much less
common in ALL in adults [8,50].
The t(1;19) occurs in two forms: a reciprocal translocation, t(1;19)(q23.3;p13.3) or, more
often, an unbalanced form characterized by two normal chromosome 1 and 19 homologs,
and a rearranged chromosome 19, der(19)t(1;19)(q23.3;p13.3) [67]. The presenting clinical
and laboratory features and event-free survival appear to be the same for these two
subtypes [67,68].
The t(1;19) involves the TCF3 (E2A) gene at 19p13.3; this gene encodes two transcription
factors (E12 and E47) that bind to enhancer elements in the IGK gene and to the regulatory
elements of other genes [69,70]. In the translocation, the TCF3 gene is juxtaposed
with PBX1, a homeobox (HOX) gene on chromosome 1. HOX genes encode DNA-binding
transcription factors that regulate developmental processes and hematopoiesis. TCF3-
PBX1 fusion mRNAs are formed and code for chimeric proteins that consist of the
transcriptional activation domain of E12/E47 and the DNA-binding and protein dimerization
domains of PBX1 [69,70]. TCF3 is expressed in all tissues; the normal PBX1 gene is
expressed in many fetal and adult tissues, but not in lymphoid cells.
How the TCF3-PBX1 fusion protein might promote leukemogenesis is not well understood.
The following possible mechanisms for transcriptional activation have been described:
●The fusion protein may directly activate gene transcription of PBX1-HOX-complex

target genes.
●The fusion protein may bind DNA cooperatively with a specific HOX protein; the
potent transactivation domain of TCF3 may then activate gene transcription.
●The PBX1-HOX complexes formed with other ubiquitously expressed PBX family
members may normally inhibit transcription; in
comparison, TCF3/PBX1/HOX complexes may induce the transcription of genes that
are normally repressed in lymphoid cells.
With each of these scenarios, the fusion protein may lead to the transactivation of a number
of genes that are not normally expressed in lymphoid tissues [71,72]. As an example, a
novel WNT gene is normally expressed in peripheral lymphoid organs but not in bone
marrow. However, high levels of WNT16 transcripts are present in bone marrow and cell
lines from patients with pre-B ALL who have the TCF3-PBX1 fusion gene; furthermore,
expression of WNT16 is reduced by inhibition of TCF3-PBX1 expression [71].
In the past, patients with the t(1;19) typically had early treatment failure, suggesting that this
translocation may distinguish a subgroup of patients who have a poor prognosis [67,68,73].
In one large study, the adverse outcome of patients with the t(1;19) remained significant
even after adjustment for recognized adverse clinical features, indicating that it is an
independent risk factor [68]. However, studies have shown that this adverse prognosis can
be overcome by more intensive chemotherapy. In the MRC/ECOG study, the event-free and
overall survival rates at five-years were 80 and 84 percent, respectively, which is
comparable to those (84 and 93 percent) with a hyperdiploid clone [13]. In fact, t(1;19),
t(12;21) and hyperdiploidy are all associated with a favorable prognosis [4].
Intrachromosomal amplification of chromosome 21 (iAMP21) — FISH analysis using

the RUNX1/AML1 and ETV6/TEL gene probes reveals multiple signals for the RUNX1 gene
in approximately 3 to 5 percent of older pediatric patients with B cell ALL. By cytogenetic
analysis, various structural abnormalities of the long arm of chromosome 21 are noted,
including an increase in the length of 21q, consistent with gene amplification [74]. Genomic
microarray studies revealed complex genomic imbalances of 21q, with multiple gains of
most of the long arm, along with deletion of the subtelomeric region [75]. Detailed analysis
revealed that breakage-fusion-bridge cycles occurred first, followed by chromothripsis,
leading to the formation of the tandem duplication(s) of 21q [76]. RUNX1 translocations or
mutations were not observed. In a series of 530 pediatric patients with B cell ALL with
iAMP21 from the United Kingdom, secondary chromosome abnormalities were common,
including gain of the X chromosome, loss of chromosome 7 or abnormalities of 7q, del(9p),
del(12p), del(13q/RB1), deletion of IKZF1, and the P2YB8-CRLF2 fusion [74]. iAMP21 was
associated with a dismal outcome, with a high risk of both early and late relapse, when
patients were treated using standard risk regimens. The poor prognosis can be overcome
by intensive treatment using high-risk regimens [74,77].
9p abnormalities in ALL — Approximately 5 to 10 percent of childhood and adult ALL
cases show a deletion of the short arm of chromosome 9. It can occur as a single
abnormality in both children and adult patients. However, it often exists as a part of a
complex clone with other numerical and structural abnormalities, in particular with a
del(12p) [78]. Loss of material from 9p can be in various forms, such as del(9p), add(9p),
der(9)t(V;9)(V;p), an isochromosome of 9q, or a dicentric chromosome with 9q.
In one study, microarray analysis and genomic DNA sequencing identified a mono-allelic
deletion of the PAX5 gene at 9p13.2 in 28 percent of ALL patients with a cryptic or a large
deletion involving 9p [79]. Deletion or mutation of the PAX5 gene results in reduced level of
the PAX5 protein or the generation of hypomorphic alleles, thereby leading primarily to loss
of function [80].
Somatically acquired mutations in the Janus kinase (JAK2) gene on chromosome band
9p24 has been reported in 18 percent of patients with Down syndrome associated ALL, but
is not commonly found in ALL patients without Down syndrome or in patients with Down
syndrome associated acute megakaryoblastic leukemia [81-83]. This JAK2 mutation (R683)
differs from the V617 mutation commonly seen in myeloproliferative neoplasms.
Deletion of 9p is an unfavorable risk factor associated with a high rate of relapse in

precursor-B ALL in children [84]. This is more pronounced in standard-risk patients defined
as those one to nine years old with WBC count below 50,000/microL [78].
In a study of 381 adult patients with precursor-B ALL, 8 percent had abnormalities in 9p
[85]. This group showed an overall survival that was significantly shorter than those with
normal karyotypes, and similar to those with poor prognosis t(9;22)/BCR-ABL1-
positive ALL.
Hyperdiploidy — Some patients with ALL have a gain of many chromosomes in the
leukemic cells with relatively few structural abnormalities. Two subgroups have been
described: a group with 1 to 4 extra chromosomes (total 47 to 50) and a more common
group that usually has 51 to 60 chromosomes but may have up to 65 chromosomes.
Chromosome 21 is gained most frequently (100 percent of cases), and multiple additional
copies of this chromosome are often seen [4,86-88]. Other frequent additional
chromosomes include the X chromosome, and chromosomes 4, 6, 10, 14, 17, and 18 [86-
88].
Structural rearrangements occur in the leukemic cells in as many of 25 percent of patients

with hyperdiploid ALL cells [88]. The most common are duplication of 1q (14 percent) and
an isochromosome of 17q (5 percent). Chromosomal translocations occur in approximately
5 to 10 percent, including t(9;22) and t(1;19).
Patients who have hyperdiploidy with more than 50 chromosomes often have all of the
clinical features that indicate a good prognosis. These include age between one and nine
years, low white blood cell count (median 6700/microL), and favorable immunophenotype
(early pre-B or pre-B) [4,13]. It has been suggested that this is not a uniform group, as the
prognosis of children with 51 to 55 chromosomes may differ from those with 56 to 65
chromosomes.
●In a series of 168 patients, the 105 patients with 51 to 55 chromosomes had a
significantly lower event-free survival at five years (72 versus 86 percent) [88]. Adverse
prognosis features within the 51 to 55 chromosome group included a higher frequency
of isochromosome 17 and a white blood cell count above 50,000 cells/microL.
Structural abnormalities did not appear to influence event-free survival, except for a
poor prognosis associated with the t(9;22).
●In another series of 541 children with hyperdiploid ALL, a higher modal number of
chromosomes (MNC) was associated with improved prognosis [89]. Estimated event-
free survival rates at six years were 80, 89, and 99 percent for cases with MNC of 51 to
53, 54 to 57, and 58 to 66, respectively. On multivariate analysis, MNC remained a
strong predictor of outcome.
Together, these studies demonstrate improved outcomes for children with hyperdiploid ALL,
especially for those with a MNC of 58 to 66.
Hypodiploidy — Approximately 5 to 6 percent of ALL patients, independent of age, have

clonal loss of various chromosomes, resulting in a hypodiploid clone with fewer than 46
chromosomes [90]. Three distinct subgroups of hypodiploidy in ALL have been identified:
●Near-haploidy (23 to 29 chromosomes)

●Low hypodiploidy (33 to 39 chromosomes)
●High hypodiploidy (42 to 45 chromosomes)
Near-haploidy is exclusively observed in children (median age of 7 years), whereas low

hypodiploidy is noted in relatively older patients (median age of 15 years) [5,90-92]. In
cytogenetic analysis, the near-haploid clone is often accompanied by a doubling of the
chromosome complement (tetraploidization) resulting in a hyperdiploid population with a
gain of two copies of certain chromosomes, which is distinguishable from the more common
hyperdiploid clone with a single gain of certain chromosomes. More detailed genetic studies
in 124 cases of hypodiploid ALL, including whole-genome and exome sequencing of 40
cases, identified differences in the genetic alterations among cases with near-haploidy and
low hypodiploidy [91]. Near-haploid cases demonstrated a higher frequency of alterations
involving tyrosine kinase signaling and Ras signaling (71 percent) and IKZF3 (13 percent),
whereas low hypodiploidy cases demonstrated alterations in TP53 (91 percent), IKZF2 (53
percent), and RB1 (41 percent). Both groups demonstrated activation of RAS signalling and
PI3K signaling pathways.
ALL patients with hypodiploid clones generally have a poor prognosis, especially patients
with near-haploid and low-hypodiploid clones. As an example, one study showed that the
three-year event-free-survival of children with near-haploid and low-hypodiploid clones was
29 percent, whereas it was 66 percent for those with high hypodiploid clones (42 to 45
chromosomes) [90]. In this regard, it is critical to avoid confusing the doubled (tetraploid)
populations of a hypodiploid clone with a true hyperdiploid population, as the prognosis is
considerably different between these cytogenetic groups. DNA index analysis and FISH
tests can help clarify such cases.
Genetic abnormalities with normal karyotype — Some cases of B cell ALL have “sub-
karyotypic” genetic abnormalities, in which aberrant gene expression or novel fusion genes
are detected without associated chromosomal abnormalities.
Gene expression — Evaluation of gene expression through gene expression profiles,

expression analyses of individual genes (eg, IKZF1), and analysis of the epigenetic
regulation of microRNAs (eg, methylation) appear to have prognostic value in patients with
ALL [79,93-100]; the clinical value of such studies is yet to be determined.
Genomewide analyses of patients with ALL have identified deletions or loss of function
mutations in genes that regulate lymphocyte development. As an example, one study
evaluated single-nucleotide polymorphism arrays and genomic DNA sequencing in 242
pediatric patients with ALL [79]. Forty percent of B-ALL cases were found to have deletion,
amplification, point mutations, or structural rearrangement in genes regulating B lymphocyte
development and differentiation. Of these, the two most frequent abnormalities were
in PAX5 and IKZF1 (in approximately 32 and 28 percent of patients, respectively). (See '9p
abnormalities in ALL' above.)
IKZF1 (IKAROS family zinc finger 1) located at 7p13 encodes the IKAROS zinc finger
binding protein that is required for normal lymphoid development [93]. Splicing
abnormalities of IKZF1 may be found in over 80 percent of patients with Philadelphia
chromosome (Ph) positive ALL and certain isoforms may be associated
with imatinib resistance in these patients [94,95]. However, abnormalities of IKZF1 may be
associated with a poor outcome independent of Ph status [101,102]. As an example, a DNA
copy number analysis of 221 patients with Ph negative high risk B-ALL (training cohort) and
258 unselected patients with B-ALL (validation cohort) reported that patients
with IKZF1 deletions had an increased frequency of relapse at 5 and 10 years and
resistance to chemotherapy [96]. The poor prognosis associated with IKZF1 abnormalities
was independent of Ph status.
Cell cycle regulatory genes — Abnormalities in cell cycle regulatory genes are also
present in ALL and may affect prognosis.
In a series of 42 patients, 85 percent had such abnormalities with 33 percent having more
than one [103]:
●RB1-Retinoblastoma gene (51 percent)

●p16 gene (also called CDKN2A and multiple tumor suppressor 1) (41 percent)
●TP53 gene (26 percent)
Patients with more than one abnormality had a significantly shorter median survival (8
versus 25 months).
In a second study in 70 patients, abnormalities (deletion, methylation) of the CDKN2B (p15)

and CDKN2A (p16) genes were noted in 69 and 39 percent, respectively [104]. On
multivariate analysis, absence of CDKN2B gene alterations was a favorable prognostic
factor for longer disease-free survival.
In a third study in 251 consecutive patients with ALL, the hypermethylation profile of cancer-
related genes was an independent prognostic factor in predicting disease-free and overall
survival [105].
Using next-generation sequencing techniques, TP53 gene mutations may be observed in

16 percent of ALL overall with higher rates in certain patient subsets [106]. The highest
rates are seen in patients with low hypodiploidy (92 percent), MYC translocations (63
percent), and complex karyotype (23 percent). In addition, the frequency
of TP53 mutations/deletions increases with age, and mutations of TP53 are higher in B-
ALL, including Burkitt leukemia, than in T-ALL (21 versus 8 percent). Clinical outcomes
were considerably worse if both TP53 genes were abnormal (eg, both mutated or one by
mutation and one by chromosomal deletion, so-called "double hits" of TP53).
BCR-ABL1-like B cell ALL — BCR-ABL1-like B cell ALL (also called Ph-like ALL) shares a
similar gene expression profile with B cell ALL with the t(9;22)/BCR-ABL1 fusion, but lacks
the BCR-ABL1 fusion or t(9;22) by cytogenetic, FISH, or molecular analysis [5,99,107]. This
subtype of ALL is detected in 10 to 13 percent of pediatric patients, 21 percent in
adolescents, and up to 33 percent of adults with B-ALL, and is resistant to standard
chemotherapy and associated with a poor prognosis [15,101,108-110]. BCR-ABL1-like B
cell ALL is mutually exclusive of the well-defined recurring chromosome abnormalities in B-
ALL, such as the t(12;21), t(4;11) and other 11q23.3/KMT2A translocations, t(1;19), and a
hyperdiploid karyotype.
Diagnosis requires the combined analysis of flow cytometry, cytogenetic and FISH patterns,
and molecular mutation and deletion studies. Detection of BCR-ABL1-like B cell ALL is
important for prognostic stratification and will become increasingly important for selection of
targeted treatment strategies.
When compared with other cases of precursor B cell ALL, this subgroup has:
●Higher median leukocyte count at presentation

●Higher median levels of minimal residual disease at the end of induction therapy
●Inferior estimated event free survival at five years – Children (58 versus 84 percent),
adolescents (41 versus 83 percent), and young adults (24 versus 63 percent)
●Inferior estimated overall survival at five years – Children (73 versus 92 percent),
adolescents (66 versus 93 percent), and young adults (26 versus 75 percent)
Larger studies that have characterized the genetic lesions in BCR-ABL1-like B cell ALL
include the following:
●Genomic profiling identified BCR-ABL1-like ALL in 264 of 1725 children, adolescents,

or young adults with precursor B cell ALL enrolled on clinical trials [15]. Analysis
identified alternative mechanisms of activated kinase signalling in 91 percent of cases,
including ABL1-class fusions, rearrangements of EPOR or JAK2, rearrangements
of CRLF2, and other changes that affect JAK/STAT or RAS pathways.
●BCR-ABL1-like ALL was identified in 20 percent of nearly 1400 consecutively
diagnosed patients with childhood B-ALL enrolled in Children's Oncology Group trials
[111]. Genetic findings included overexpression and rearrangement of CRLF2 in 44
percent, with concomitant genomic alterations activating the JAK-STAT pathway in half
of those children. Other molecular lesions involved fusions of ABL-class
genes, EPOR rearrangements, JAK2 fusions, alterations of other JAK-STAT signaling
genes, and mutations involving the RAS pathway.
●BCR-ABL1-like B-ALL is also seen in adult patients. Among 798 adult patients with B-
ALL, this entity was identified in 28 percent of patients of age 21 to 39, 20 percent of
patients of age 40 to 59, and 24 percent of patients of age 60 to 89 [109]. Kinase-
activating alterations were present in 88 percent of these cases,
including CRLF2 rearrangement in just over half. Similarly, in another study of 148
adult patients with B-ALL, 49 (33 percent) patients showed BCR-ABL1-like gene
expression features, with 61 percent of patients involving CRLF2 overexpression and
rearrangement [110]. These patients, particularly those with CRFL2 rearrangements,
had significantly worse overall survival and event free survival compared with other
patients with B-ALL and no BCR-ABL1-like abnormalities.
Genes that are mutated in BCR-ABL1-like B-ALL generally encode proteins involved in B
cell development, proliferation and differentiation, cell cycle regulation, and cell signaling.
These mutations result in constitutive kinase activation and signaling via activation of the
ABL1 and JAK-STAT pathways, which are sensitive to tyrosine kinase inhibitors or JAK
kinase inhibitors [15,112,113]. Prospective studies are needed to determine the efficacy of
these agents in this patient population.
In approximately 50 percent of patients with the BCR-ABL1-like B cell ALL, the cytokine
receptor-like factor 2 (CRLF2) gene within the pseudo-autosomal region 1 (PAR1) of the
short arm of the X or Y chromosome is involved in a cryptic translocation with the IGH gene
at 14q32.3 (ie, t(X;14) or t(Y;14)), or is fused with the P2RY8 gene via small interstitial
deletions within the PAR1 locus [15,83,101]. Both chromosome translocations and the
interstitial deletion lead to CRLF2 overexpression due to juxtaposition with the enhancer
of IGH or the promoter of the P2RY8 gene. Rarely, gain-of-function point mutations of
the CRLF2 gene or gain of extra copies of the CRLF2 locus can result in its overexpression.
In approximately 30 to 55 percent of these patients, mutations in JAK2 or JAK1 or in IL7R,
FLT3, SH2B3, or NRAS are detected, indicative of the cooperation of these kinase-
activating lesions with CRLF2 rearrangement in leukemogenesis [15,108]. In addition,
deletions involving part or all of the IKZF1 locus, the PAX5 locus, and the EBF1 gene are
frequently detected in these patients. Almost all patients with Down syndrome-related B cell
ALL will have a deletion of IKZF1 [83,108].
In the remaining BCR-ABL1-like B cell ALL cases with no CRLF2 overexpression, other
tyrosine kinase targets, such as ABL1, ABL2, JAK2, EPOR, and PDGFRB, are activated via
various translocations and fusions, such as the NUP214-ABL1, BCR-JAK2, STRB3-JAK2,
IGH-EPOR, and EBF1-PDGFRB fusions [15,113]. In addition, mutations of FLT3, CREBBP,
IL7R, or SH2B3 (LNK) occur frequently in these patients.
Recurring gene fusions — Up to 30 percent of B-ALLs are not defined by current WHO
genetic subgroups (ie, they do not have recurring chromosome abnormalities, kinase
activating gene fusions, or Ph-like B-ALL). Next generation sequencing of RNA and other
genomic studies have revealed several recurring genetic abnormalities in this category of B-
ALL in adolescent and young adult patients. Examples include:
●MEF2D-BCL9 fusion - The myocyte enhancer factor 2D (MEF2D) gene encodes a

transcription factor that participates in neuronal development and myogenesis. Fusion
of MEF2D with BCL9 (or one of a few other genes) was detected in 5 to 7 percent of
patients with B-ALL, mostly in adolescents [114,115]. B-ALL with the MEF2D-
BCL9 fusion is characterized by a distinct immunophenotype, similar to that of ALL with
the t(1;19), markedly high expression of HDAC9, resistance to chemotherapy, early
relapse, and a poor outcome.
●DUX4-ERG or DUX-IGH fusion - The double homeobox 4 gene (DUX4) is located
near the telomere of the long arm of chromosome 4, and encodes the transcriptional
activator PITX1. DUX4-IGH or DUX4-ERG fusions were detected in about 4 to 7
percent of pediatric and young patients with B-ALL [116-119]. The DUX4-
IGH translocation leads to overexpression of an altered DUX4 protein with an aberrant
carboxy terminus, which induces B cell leukemia in mice. Nearly all patients
with DUX4 aberrations also show deletion of ERG, indicative of the cooperation
of DUX4 and ERG in mediating leukemogenesis.
●EP300-ZNF384 and CREBBP-ZNF384 fusions - The zinc finger 384 protein
(ZNF384) regulates expression of genes encoding extracellular matrix proteins.
An EP300-ZNF384 or CREBBP-ZNF384 fusion is detected in 7 to 12 percent of
adolescent and young adult patients with B-ALL; the disease is CD10-negative, and is
characterized by high expression of GATA3, CEBPA, and CEBPB, upregulated JAK-
STAT signaling, and a relatively low frequency of mutations or deletions of B cell
development-related genes, such as IKZF1, PAX5, RUNX1, ETV6, or cell cycle
regulators CDKN2A/CDKN2B [119,120].
T CELL ACUTE LYMPHOBLASTIC LEUKEMIA — Patients with T cell ALL are most often
young males. They have a number of unfavorable presenting characteristics, including a
mediastinal tumor mass, high white blood cell count (≥50,000/microL), and leukemic cells in
the cerebrospinal fluid [121-123]. These characteristics are also associated with T cell
lymphoblastic lymphoma, a related T cell malignancy. (See "Clinical manifestations,
pathologic features, and diagnosis of precursor T cell acute lymphoblastic
leukemia/lymphoma".)
Genetic abnormalities — Among children with T-ALL, approximately 60 percent have an

abnormal karyotype [122]. These patients have a distinct pattern of recurring karyotypic
abnormalities involving both T cell receptor (TCR) and non-TCR gene loci [121,122,124-
126].
TCR gene rearrangements — The most common rearrangements involve the proximal
bands of chromosome 14 (14q11.2) and two regions of chromosome 7 (7q34 and 7p14).
These rearrangements occur at the locations of the T cell receptor (TCR) genes [127,128]:
●TCR alpha/delta chain at 14q11.2 (TRA/TRD)

●TCR beta chain at 7q34 (TRB)
●TCR gamma chain at 7p14 (TRG)
With few exceptions, the involved gene on the partner chromosome encodes a cell cycle
inhibitor or a transcription factor whose expression is deregulated or activated as a result of
the rearrangement [121,125,129].
Oncogenes typically involved in TCR gene rearrangements may be overexpressed by other

mechanisms. As an example, two children with X-linked severe combined
immunodeficiency who received gene therapy using a provirus developed a T cell acute
leukemia-like syndrome [126]. The provirus was integrated within the LMO2 gene locus
(11p13), which encodes one of the oncogenes frequently involved in TCR gene
rearrangements (eg, t(11;14), t(7;11)). (See "Hematopoietic cell transplantation for primary
immunodeficiency".)
Non-TCR loci — A variety of karyotypic and/or mutational abnormalities can occur in T cell
ALL that do not involve the T cell receptor (TCR) loci, including [122]:
●del(6q)
●t(11q23.3) (KMT2A gene)
●t(14q32.3)
●Trisomy 8
●t(10;11)/PICALM-MLLT10 fusion [130]
●Gain-of-function NOTCH1 mutations or loss-of-function FBXW7 mutations [131-135]
●JAK1 or JAK3 mutations [136,137]
●Overexpression of the TLX1 (HOX11) oncogenic transcription factor [138-140]
NOTCH1 signalling is necessary for commitment to the T cell lineage and for the
proliferation of T cell progenitors in the thymus. It has been estimated that activating
mutations of NOTCH1 are present in more than 50 percent of patients with T cell ALL [131].
Although the precise mechanisms by which NOTCH1 causes T cell ALL are not yet fully
elucidated, studies suggest interaction between NOTCH1 and components of the polycomb
repressive complex 2 (PRC2), a highly conserved complex that influences stem cell renewal
by epigenetic repression of genes involved in cell fate decisions [141]. Deletion of
the NOTCH1 promoter can also result in activation of the Notch1 gene from cryptic initiation
sites [142,143]. Spontaneous deletion of the NOTCH1 locus is seen in approximately 75
percent of IKZF1-deficient T cell ALL cases [142]. Patients with T cell ALL demonstrating
a NOTCH1 mutation or a related mutation in FBXW7 may represent a subset with superior
event-free and overall survival rates when compared with other patients with T cell ALL
[135,144-146].
MicroRNAs (miRNAs) are a novel class of small noncoding RNAs that modulate the
expression of genes at the post-transcriptional level, and are involved in cancer, apoptosis,
and cell metabolism. They may have particular relevance to T cell ALL. Expression profiles
in human T-ALL have identified a small number of abundantly expressed miRNAs that
target a set of tumor suppressor genes (IKZF1, PTEN, BIM, NF1, FBXW7, and PHF) and
promote T-ALL in mice [147]. Specifically, mir-223 is differentially upregulated in T cell ALL
and appears to promote NOTCH1-driven leukemia.
Recurrent mutations of loci located on the X chromosome have been identified in patients
with T cell ALL and offered as a possible explanation for the increased incidence of this
disease in males. As an example, inactivating mutations or deletions in the plant
homeodomain finger 6 (PHF6) locus located on the X chromosome are found in 16 percent
and 38 percent of primary T cell ALL in children and adults, respectively [148]. Loss
of PHF6 is associated with aberrant expression of the TLX1 (HOX11) transcription factor
oncogene. Similarly, a small percentage of cases will demonstrate mutations in the
ribosomal gene RPL10 located on the X chromosome [149]. However, mutations in many of
these loci (eg, PHF6, RPL10) cannot be used to explain the difference in incidence between
males and females because they are located in regions that undergo X inactivation in
females. In contrast, at least part of the sex predilection may be explained by mutations
in UTX (also known as KDM6A), a tumor suppressor located in a region of chromosome X
that escapes X inactivation in females [150,151]. (See "Clinical manifestations, pathologic
features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma",
section on 'Epidemiologic data'.)
Up to 15 percent of T cell ALL lack expression of CD1a and CD8 and have weak expression
of CD5 [152]. This subtype, termed “early T cell precursor ALL”, has a significantly higher
rate of treatment failure. Whole genome sequencing of tumor cells from 12 patients with
early T cell precursor ALL demonstrated a high frequency of somatic mutations involving
the pathways of normal hematopoietic development, RAS signalling, and histone
modification, similar to those more frequently involved in acute myeloid leukemias [153].
Prognosis — Both children and adults with T cell ALL are generally treated with high-risk
protocols and often have favorable outcomes [122,154]. At least in children, the type or
presence of karyotypic abnormalities does not appear to affect prognosis, as patients with
any of the above translocations have an outcome similar to those with normal karyotype
[122]. One study found that T cell ALL with low expression of both ERG and BAALC genes
by RT-PCR is associated with significantly lower relapse rates (17 versus 60 percent) and
higher four-year overall survival (69 versus 30 percent) [155]. How to apply this information
clinically is unclear at this time.

materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are
on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Acute lymphoblastic leukemia
(ALL) treatment in adults (Beyond the Basics)")
SUMMARY
●Cytogenetic analysis and molecular cytogenetic studies, such as fluorescence in situ

hybridization (FISH), reveal recurring chromosome abnormalities in approximately 80
percent of B cell acute lymphoblastic leukemia (ALL), including numerical and
structural changes, such as translocations, inversions, or deletions. There are
substantial differences between children and adults with ALL in the frequencies of
recurring abnormalities. (See 'B cell acute lymphoblastic leukemia' above.)
●The t(12;21), resulting in the fusion ETV6/RUNX1 gene, is detectable by FISH or
polymerase chain reaction analysis in about 25 percent of children with B-lineage ALL
and 3 percent of adults with ALL. Patients with ALL and the t(12;21) generally have a
favorable prognosis. (See '12;21 translocation in precursor B ALL' above.)
●The t(8;14), present in a high proportion of Burkitt cell leukemia/lymphoma, occurs in
approximately 1 percent of adults with ALL. This translocation is associated with
lymphoblasts with deeply basophilic cytoplasm with prominent vacuoles, a high
incidence of central nervous system involvement at diagnosis, and a poorer prognosis
than any other group of patients classified by chromosomal abnormalities. (See '8;14
translocation' above.)
●The t(4;11) is present in up to 60 percent of infants with ALL younger than 12 months,
but is rarely observed in adult patients with ALL. This translocation results in a KMT2A-
AFF1 fusion gene, and is associated with a poor prognosis in both adults and children.
ALL with the t(4;11) is commonly characterized by high leukocyte counts, an immature
immunophenotype, B cell lineage, and frequent co-expression of myeloid antigens.
(See '4;11 translocation' above.)
●Translocations involving 11q23.3 are seen in 60 to 80 percent of ALL in infants, and
cause abnormalities of KMT2A, which encodes a histone methyltransferase that
regulates gene transcription via chromatin remodeling. Leukemias
with KMT2A translocations have a characteristic and distinctive gene expression
profile. ALL in infants and children with KMT2A translocations is associated with a high
rate of early treatment failure and a very poor outcome. (See '11q23.3 translocation in
infants' above.)
●The t(9;22) that produces the Philadelphia chromosome is observed in about 2 to 5
percent of children and about 30 percent of adults. This translocation is associated with
a poor prognosis. Treatment of patients with the t(9;22) incorporates tyrosine kinase
inhibitors that target the BCR-ABL1 protein, which is the fusion product of the
Philadelphia chromosome. (See '9;22 translocation' above.)
●The t(1;19) occurs in approximately 30 percent of patients with pre-B cell childhood
ALL and less commonly in other B lineage ALLs in children and adults. In the past,
patients with the t(1;19) typically had early treatment failure. However, this adverse
prognosis can be overcome by more intensive chemotherapy such that t(1;19) is now
associated with a favorable prognosis. (See '1;19 translocation in pre-B cell
ALL' above.)
●Patients who have hyperdiploidy with more than 50 chromosomes often have a good
prognosis. The individual structural abnormalities do not appear to influence outcome
in patients with hyperdiploidy except for the t(9;22), which is associated with a poor
prognosis. (See 'Hyperdiploidy' above.)
●Approximately 5 to 6 percent of ALL patients, independent of age, have clonal loss of
various chromosomes, resulting in a hypodiploid clone with fewer than 46
chromosomes. ALL patients with hypodiploid clones generally have a poor prognosis,
especially patients with near-haploid and low-hypodiploid clones. Similarly, deletion of
9p is an unfavorable risk factor associated with a high rate of relapse in precursor-B
ALL in children. (See 'Hypodiploidy' above and '9p abnormalities in ALL' above.)
●BCR-ABL1-like (also known as Ph-like) B cell ALL has a gene expression profile that
resembles B cell ALL with the t(9;22)/BCR-ABL1 fusion, but the fusion oncogene is not
present. This phenotype is detected in 10 to 15 percent of pediatric patients and up to
28 percent of adult patients with B cell ALL, is resistant to standard chemotherapy, and
is associated with a poor prognosis. Translocations involving CRLF2,
or mutations/rearrangements of other tyrosine kinase targets (eg, ABL1, ABL2, JAK2,
PDGFRB) activate ABL1, JAK-STAT, or RAS pathways that are involved in B cell
development, proliferation, and differentiation. Some of these cases of ALL are
sensitive to tyrosine kinase inhibitors or JAK kinase inhibitors. (See 'BCR-ABL1-like B
cell ALL' above.)
●Up to 30 percent of B-ALLs are not defined by existing WHO subgroups (ie, they do
not have recurring chromosome abnormalities, kinase activating gene fusions, or Ph-
like B-ALL). Several recurring genetic abnormalities in this category of B-ALL in
adolescent and young adult patients have been identified recently, including
the MEF2D-BCL9, DUX4-ERG or DUX-IGH, and EP300-ZNF384 and CREBBP-
ZNF384 fusions. (See 'Recurring gene fusions' above.)
●Among children with T cell ALL, approximately 60 percent have an abnormal karyotype.
These patients have a distinct pattern of recurring karyotypic abnormalities involving both T
cell receptor (TCR) and non-TCR gene loci, including activating mutations of NOTCH1 in
more than 50 percent. Both children and adults with T cell ALL are generally treated with
high-risk protocols and often have favorable outcomes. (See 'T cell acute lymphoblastic
leukemia' above.)
INTRODUCTION — Acute leukemia is the most common form of cancer in children,

comprising approximately 30 percent of all childhood malignancies [1]. Of the acute
leukemias, acute lymphoblastic leukemia (ALL) occurs five times more commonly than
acute myeloid leukemia (AML). Survival rates for ALL have improved dramatically since the
1980s, with current five-year overall survival rates estimated at greater than 85 percent [1-
4]. Five-year event-free survival rates are >93 percent for low-risk groups [5]. This
improvement in survival is due to treatment of a large number of children on sequential
standardized research protocols. Approximately 75 to 80 percent of children with newly
diagnosed ALL participate in such trials, the goals of which are to improve clinical outcomes
while minimizing acute toxicities and late-occurring adverse events.
The treatment of ALL in children is reviewed here. The epidemiology, presentation,

classification, risk group stratification, and outcome of childhood ALL are discussed
separately. (See "Overview of the presentation and diagnosis of acute lymphoblastic
leukemia in children and adolescents" and "Risk group stratification and prognosis for acute
lymphoblastic leukemia in children and adolescents" and "Overview of the outcome of acute
lymphoblastic leukemia in children and adolescents".)
Although the majority of children with ALL will be cured, consultation with palliative care
specialists may be considered at the time of diagnosis as with any life-threatening condition
or for pain management. (See "Pediatric palliative care".)
OVERVIEW OF TREATMENT — Successful treatment of children with ALL involves

administration of a multidrug regimen that is divided into several phases (ie, induction,
consolidation, and maintenance) and includes therapy directed to the central nervous
system (CNS). Most treatment protocols take two to three years to complete, although the
specific regimen varies depending upon immunophenotype and risk category (table 1).
(See "Risk group stratification and prognosis for acute lymphoblastic leukemia in children
and adolescents".)
At the time of diagnosis, patients with ALL commonly require transfusion support, treatment
of suspected or proven infections with broad-spectrum antibiotics, and, for patients with a
high tumor burden, correction of any metabolic imbalances such as hyperuricemia. A rare
patient may require leukapheresis or exchange transfusion to control extreme leukocytosis.
(See "Red blood cell transfusion in infants and children: Indications" and "Uric acid renal
diseases", section on 'Acute uric acid nephropathy' and "Hyperleukocytosis and leukostasis
in hematologic malignancies".)
Despite improvements in supportive care, death resulting from treatment toxicity remains a
challenge. In a review of over 1000 children with ALL treated at St. Jude Children's
Research Hospital, the estimated 10-year cumulative incidence of treatment-related death
was 2.9 percent [6]. Age was the only predictor of death; children in the age bracket from
one to nine years had a significantly lower risk of treatment-related mortality than did either
infants or older children. In a subsequent retrospective analysis of 8516 children ages 0 to
19 years of age with newly-diagnosed ALL treated at US institutions, induction mortality was
1.12 percent [7]. Induction mortality was not associated with race or socio-economic status,
but was increased among children age <1 year (hazard ratio [HR] 3.34, 95% CI 1.22-9.13)
and 10 to 19 years (HR 2.89, 95% CI 1.55-5.41) and among those with cardio-respiratory or
other organ failure (HR 145.4, 95% CI 37.8-145.4).
INDUCTION THERAPY
Regimen — Induction therapy is the initial phase of treatment. The primary goal of
induction is achievement of an initial complete remission (CR), defined as the eradication of
all detectable leukemia cells (less than 5 percent blasts) from the bone marrow and blood
and the restoration of normal hematopoiesis (>25 percent cellularity and normal peripheral
blood counts). The induction therapy given differs depending upon whether a t(9;22)
translocation (Philadelphia chromosome) is present. While t(9;22) translocation is
uncommon in children, those with this translocation benefit from the addition of a tyrosine
kinase inhibitor that targets the aberrant expression of BCR-ABL1.
t(9;22)/BCR-ABL1 negative ALL — More than 90 percent of children and adolescents with
ALL enter complete remission (CR) at the end of induction therapy regardless of their initial
risk grouping [8-17].
Induction therapy usually involves weekly administration of vincristine for three to four
weeks, daily corticosteroids (prednisone, prednisolone, or dexamethasone), and
asparaginase. Asparaginase is available as an E. coli derivative, either in its native form (L-
asparaginase) or in its pegylated form (Oncaspar) [18]. The pegylated form results in a
longer period of asparagine depletion with comparable toxicity [19]. L-asparaginase is no
longer available for use in the United States. For patients with E. coli asparaginase
allergies, asparaginase is also available from Erwinia (Erwinase) [20]. A fourth agent such
as an anthracycline (eg, doxorubicin or daunorubicin) may be added to the three-drug
regimen, particularly for high-risk patients.
Response to therapy is often assessed by bone marrow examination during the induction
phase of treatment. In addition to morphologic response, bone marrow aspirates are also
assessed for the presence of minimal residual disease (MRD). Assessments can be
performed by either quantitative polymerase chain reaction (PCR) or by flow cytometry [21-
23]. Both methods have shown that end-of induction and end-of consolidation bone marrow
MRD strongly correlate with survival [5,24,25]. (See "Clinical use of minimal residual
disease detection in acute lymphoblastic leukemia", section on 'MRD in children'.)
Early clearance of lymphoblasts from peripheral blood during the first week of therapy,
clearance of blasts from the bone marrow by the end of induction, and the presence or
absence of MRD at the end of induction therapy are important indicators of outcome.
Patients who respond rapidly to the induction regimen appear to have a more favorable
outcome, whereas those who have a slow response or who fail induction therapy have a
more guarded prognosis [5,21-25]. This is discussed in more detail separately.
(See "Clinical use of minimal residual disease detection in acute lymphoblastic leukemia",
section on 'MRD in children'.)
t(9;22)/BCR-ABL1 positive ALL — The t(9;22) translocation (Philadelphia chromosome) is

a rare mutation in children with ALL, with an incidence rate of <5 percent. Although
the t(9;22)/BCR-ABL1 translocation was formerly associated with a very poor prognosis,
outcome has significantly improved with the introduction of tyrosine kinase inhibitors (TKI),
such as imatinib or dasatinib, to therapy regimens [26-30]. In a prospective clinical trial from
the Children's Oncology Group (COG), 91 children (age 1 to 21 years) with Philadelphia
chromosome positive ALL were treated with intensive chemotherapy plus imatinib [30].
Those treated from induction until the completion of therapy with imatinib had the best
outcome, with a five-year disease-free survival (DFS) of 70 percent. DFS was not
statistically different between patients treated with chemotherapy plus imatinib (70±12
percent, n = 28) versus those who underwent sibling donor hematopoietic cell transplant
(HCT) (65±11 percent, n = 21) or those receiving an unrelated donor HCT (59±15 percent,
n = 13).
Patients with trisomy 21 — Patients with trisomy 21/Down syndrome who develop ALL
(DS-ALL) are particularly susceptible to adverse events and treatment-related mortality.
Intensive chemotherapy regimens with high-dose methotrexate frequently result in severe
mucositis, and children with DS-ALL have an increased risk of severe infections [31]. An
analysis of 653 children with DS-ALL demonstrated that these patients have both a high
rate of relapse (26 percent eight-year cumulative relapse incidence) and an increased rate
of two-year treatment-related mortality (7 versus 2 percent in non-DS-ALL) [32].
(See "Overview of the outcome of acute lymphoblastic leukemia in children and
adolescents", section on 'Down syndrome'.)
Because of the increased incidence of infectious deaths in DS-ALL throughout all stages of
chemotherapy treatment (induction, consolidation, and maintenance) [33], patients are often
treated on protocols with reduced intensity chemotherapy, usually without evidence of
inferior outcome [34]. In general, many patients can be cured without the use of
hematopoietic cell transplantation (HCT), which has been associated with high treatment
mortality.
Although cytogenetic changes other than trisomy 21 are uncommon with DS-ALL, those
with concurrent low-risk cytogenetics (ETV-RUNX1) comprise a risk group with an
exceptionally good prognosis (eight-year event-free survival 95±4 percent). This group,
although uncommon, can be treated with less intense chemotherapy [32]. Those with high-
risk features can be successfully treated with reduced-intensity conditioning followed by
HCT. Outcomes, however, remain poor with three-year EFS of only 24 percent [35].
Asparaginase inactivation and therapeutic drug monitoring — Between 2 to 8 percent

of patients receiving E. coli asparaginase develop silent inactivation due to the production of
neutralizing anti-asparaginase antibodies [36,37]. Therapeutic drug monitoring of
asparaginase activity can accurately determine if a patient has neutralizing antibodies that
are inactivating the target enzymatic activity of asparaginase [37]. Those with neutralizing
antibodies have asparaginase activity well below the therapeutic threshold and can often be
treated with Erwinia asparaginase as an effective alternative since there is only
approximately 10 percent antibody cross-reactivity between E. coli and Erwinia
asparaginase preparations [38]. (See "Infusion reactions to systemic chemotherapy",
section on 'Formulations'.)
A retrospective study of 763 pediatric patients with ALL examined therapeutic drug
monitoring and suggested that lower doses of PEG-asparaginase can be used to maintain
asparagine depletion [39]; these results will need to be confirmed in prospective clinical
trials. It is currently unknown if decreasing the asparaginase dose will result in fewer
thrombotic or hemorrhagic complications. (See 'Thrombosis' below.)
Adverse effects — Some children with ALL experience significant adverse effects during
induction chemotherapy. Toxicity can result from the chemotherapeutic agents or from the
rapid elimination of a large tumor burden (ie, tumor lysis syndrome). Life-threatening
adverse effects of induction therapy include tumor lysis syndrome, thrombosis, bleeding,
and infection. Other acute side effects include mucositis, pancreatitis, and hyperglycemia.
Late effects of chemotherapy are discussed separately. (See "Overview of the outcome of
acute lymphoblastic leukemia in children and adolescents", section on 'Late effects'.)
Tumor lysis syndrome — Acute tumor lysis syndrome is the term applied to a group of
metabolic complications that may occur after the treatment of neoplastic disorders. The
findings that may be seen include hyperphosphatemia, hypocalcemia (caused by
precipitation of calcium phosphate), hyperuricemia, hyperkalemia, and acute renal failure.
Rapid leukemic cell lysis after chemotherapy can cause over-production and over-excretion
of uric acid. The precipitation of uric acid in the tubules can lead to oliguric or anuric renal
failure known as uric acid nephropathy [40]. (See "Tumor lysis syndrome: Definition,
pathogenesis, clinical manifestations, etiology and risk factors" and "Acute kidney injury in
children: Clinical features, etiology, evaluation, and diagnosis".)
In a study of 328 children with ALL, the following four factors were identified as independent
predictors of tumor lysis syndrome on multivariate analysis [41]:
●Age >10 years

●Splenomegaly
●Mediastinal mass
●Initial white blood cell count >20,000/microL
Absence of all four of these risk factors indicated a low risk for development of tumor lysis
syndrome, with a negative predictive value of 98 percent and a sensitivity of 96 percent.
Prophylactic regimens to prevent acute uric acid nephropathy in children with ALL include
the administration of medications to reduce the production of uric acid
(allopurinol or rasburicase, a recombinant uricase that catalyzes oxidation of uric acid to the
much more soluble compound allantoin), and aggressive intravenous hydration [42].
Hemodialysis may be necessary to remove excess circulating uric acid and phosphate in
patients who develop acute renal failure and in whom adequate diuresis cannot be
achieved. These issues are discussed in detail separately. (See "Tumor lysis syndrome:
Prevention and treatment", section on 'Clinical impact of TLS'.)
Adverse effects of rasburicase include allergic reactions, including anaphylaxis, hemolysis,

hemoglobinuria, methemoglobinemia, and interference with uric acid measurements [43].
This agent is contraindicated in patients with glucose-6-phosphate dehydrogenase
deficiency because it can cause severe hemolysis [43].
Thrombosis — Thrombotic events, including intracranial dural sinus thrombosis with

hemorrhage, deep vein thrombosis, and pulmonary embolism, have been reported with
induction chemotherapy regimens for ALL that include all forms of asparaginase [44].
Thrombosis is a major complication that may be life-threatening and impact future therapy.
In contemporary treatment protocols, the incidence of thrombotic complications among
children with ALL receiving asparaginase has varied among studies from as low as 1.8
percent to as high as 15 percent in children with prothrombotic risk factors [45]. Increased
risk of thrombosis occurs with increased age and the presence of a central venous catheter
[46,47].
In a prospective trial of children and adolescents with ALL, thrombosis occurred in 63 of

1038 (6 percent) and was most common among those age 15 years and older (21 percent)
[47]. Most thromboses were in the setting of asparaginase administration. Nine children
died within 30 days of thrombosis with four deaths directly attributable to the thrombosis. In
addition, approximately half of patients alive after thrombosis had delays or dose
modifications of further asparaginase therapy.
A 2006 meta-analysis of 1752 children with ALL reported that 5.2 percent of patients
developed a thrombosis at some time during treatment (ie, from the start of induction
through the end of maintenance) [48]. Most (83 percent) of these events occurred during
induction therapy. The following four risk factors for thrombosis were identified in this
population:
●Treatment with asparaginase

●Concomitant use of steroids
●Thrombophilic genetic abnormalities
●Presence of central venous lines
In a European study, these risk factors were used to develop a predictive model for
identifying children with ALL at the highest risk of thrombosis during induction with
asparaginase-based therapy [49]. While the 2006 meta-analysis did not evaluate the impact
of ABO blood group on the risk of thrombosis, a subsequent large retrospective analysis
reported an association between non-O blood group and age and an increased risk of
thrombosis [50]. Non-O blood type is a known risk factor for VTE in adults. (See "Overview
of the causes of venous thrombosis", section on 'Non-O blood type'.)
A retrospective analysis of 336 consecutively recruited children with ALL treated on different
Berlin-Frankfurt-Munster (BFM) study protocols found a lower incidence of
thromboembolism when asparaginase was used in conjunction with dexamethasone rather
than prednisone (1.8 versus 10.4 percent) [51]. The results of this study, limited by the small
number of patients (n = 56) in the dexamethasone treatment group, bear further scrutiny in
prospective trials with larger numbers of patients.
Asparaginase depletes plasma asparagine, thereby inhibiting protein synthesis in leukemic
cells and the synthesis of several plasma proteins. The latter effect causes deficiencies of
albumin, thyroxine-binding globulin, and various coagulation proteins, including
prothrombin, factors V, VII, VIII, IX, X, XI, fibrinogen, antithrombin, protein C, protein S, and
plasminogen [52,53]. These deficiencies result in prolongation of the prothrombin time,
activated partial thromboplastin time (aPTT), thrombin time, and hypofibrinogenemia, with
fibrinogen levels often less than 100 mg/dL. E. coli-asparaginase and Erwinia-asparaginase
appear to have equivalent risk of severe thrombosis, including central nervous system
hemorrhage. (See "Drug-induced thrombosis in patients with malignancy", section on 'L-
asparaginase' and "Antithrombin deficiency", section on 'Patients receiving asparaginase'.)
Bleeding — Hemorrhage in children with ALL usually is caused by thrombocytopenia.

Patients who have platelet counts <10,000/microL are at greatest risk. Children with
thrombocytopenia typically have bleeding from the skin or mucus membranes; significant
visceral bleeding is unusual. Intracranial hemorrhages are rare but life-threatening events.
Treatment or prevention of such bleeding is provided by transfusion of platelets.
(See "Clinical and laboratory aspects of platelet transfusion therapy", section on 'Leukemia,
chemotherapy, and HCT'.)
Patients who require prolonged antibiotic therapy may develop bleeding secondary to a
vitamin-K dependent coagulopathy. Patients with an elevated prothrombin time (PT) are
treated with oral or intravenous vitamin K (2.5 to 5.0 mg PO per day; or if bleeding, 1 to 2
mg IV as a single dose). (See "Beta-lactam antibiotics: Mechanisms of action and
resistance and adverse effects", section on 'Hematologic reactions'.)
Infection — Children with newly diagnosed ALL are functionally neutropenic and
lymphopenic at the time of diagnosis and may develop further myelosuppression following
chemotherapy. These children are more susceptible to development of systemic bacterial,
fungal, and viral infections (eg, varicella-zoster, herpes simplex virus). Infections account for
the majority of treatment-related mortality in this population.
As an example, in a retrospective review of 425 children who received induction therapy for
ALL at a single tertiary Canadian center, 20 percent of all patients experienced at least one
documented infection [54]. Neutropenia was almost twice as common in those who
developed infections compared with those without infection. Patients with pre-existing
conditions (ie, Down syndrome, congenital heart disease, pre-existing immunodeficiency
syndromes) were at highest risk of infections. The 85 infections included 65 bacterial, 15
viral, and 5 fungal infections. Infectious mortality was minimal (3 out of 425, or 1 percent)
and included deaths from both fungal (Candida albicans) and bacterial (Bacillus cereus)
infections.
Details regarding infection-related deaths are also available from the prospective UKALL
2003 trial, which reported 75 septic deaths among 3126 children (2.4 percent) with newly
diagnosed ALL, accounting for 64 percent of treatment-related mortality [33]:
●Although infection-related mortality was most common during induction therapy (48
percent), it also occurred during consolidation (9 percent), delayed intensification (23
percent), and maintenance therapy (20 percent). Underlying Down syndrome was
associated with a significantly increased risk of death due to sepsis (odds ratio 12)
during all treatment periods. (See 'Patients with trisomy 21' above.)
●Most deaths occurred in neutropenic patients and within 48 hours of presentation with
sepsis.
●Most septic deaths with an identified pathogen were due to bacteria (68 percent), with
fungal (20 percent) and viral (12 percent) pathogens being less common. The most
commonly identified bacteria were Pseudomonas, E. coli, and Enterococcus.
Because these infections are potentially life-threatening in any phase of therapy, fever in
children who are receiving chemotherapy must be evaluated and aggressively treated. The
use of prophylactic antimicrobial therapy is recommended, but the specific therapy varies by
circumstance and institution. For example, the use of an antimicrobial (sulfamethoxazole-
trimethoprim, dapsone, or pentamidine) Pneumocystis pneumonia prophylaxis is almost
universal in the management of patients receiving chemotherapy, while the administration
of antifungals and antiviral agents is more individualized. (See "Fever in children with
chemotherapy-induced neutropenia".)
The role of colony-stimulating factors (granulocyte colony-stimulating factor and granulocyte

macrophage colony-stimulating factor) to prevent or manage infectious complications during
ALL induction has not been well studied. In one randomized, crossover study in 287
children with high-risk ALL, prophylactic use of granulocyte colony-stimulating factor
shortened periods of neutropenia, but did not reduce rates of febrile neutropenia, serious
infections, or the need for hospitalization; overall survival at six years was not affected [55].
A systematic review has come to similar conclusions [56].
Neuropathy — Virtually all patients receiving vincristine have some degree of neuropathy
and approximately 25 to 30 percent of children treated for ALL will develop clinically
significant peripheral neuropathy requiring dose reduction or treatment discontinuation. The
rate may be significantly higher in patients with a genetic predisposition (eg, single
nucleotide polymorphism in the promoter region of CEP72) [57]. The neuropathy involves
both sensory and motor fibers and can manifest as paresthesias, loss of reflexes,
weakness, and autonomic neuropathies, including vocal cord paralysis. Patients with mild
neuropathy can usually continue to receive full doses of vincristine, but when symptoms
increase in severity and interfere with activities of daily living, dose reduction or
discontinuation of the drug may be necessary. Vincristine neuropathy is usually reversible
but improvement is gradual and may take up to several months. This is described in more
detail separately. (See "Overview of neurologic complications of non-platinum cancer
chemotherapy", section on 'Vincristine'.)
Anaphylaxis — Some chemotherapy and supportive medications, such as asparaginase,

the epipodophyllotoxins (etoposide and etopophosphamide), and uricase, can cause
significant allergic reactions, including anaphylaxis. Medications used to treat anaphylaxis
should be readily available when these drugs are administered. Anaphylactic reactions to
PEG-asparaginase can be delayed by several hours. Because of this delay, a period of
observation following administration of PEG-asparaginase has become common practice at
many institutions. (See "Infusion reactions to systemic chemotherapy", section on 'L-
asparaginase'.)
HPA axis suppression — The administration of daily corticosteroids during induction

therapy results in suppression of the hypothalamic-pituitary-adrenal (HPA) axis in most
patients [58]. A study of 64 patients showed that over 80 percent of children had significant
suppression of cortisol release by adrenocorticotropic hormone (ACTH) stimulation [59]. In
this study, all patients had recovered normal adrenal function by 10 weeks following
induction chemotherapy. Because nearly all patients experienced adrenal insufficiency
during the first days after cessation of glucocorticoid treatment, it is recommended that
children with infections, trauma, or surgery occurring during or shortly after induction be
treated with glucocorticoid replacement. While the majority recovers HPA axis function
within a few weeks after corticosteroid cessation [59], HPA axis suppression lasted up to 34
weeks in one analysis [60]. For this reason, glucocorticoid replacement following trauma,
infection, or surgery should be considered on a case-by-case basis for children with ALL
following induction. (See "Glucocorticoid withdrawal", section on 'Hypothalamic-pituitary-
adrenal axis suppression' and "Diagnosis of adrenal insufficiency in children".)
Induction failure — Induction failure, which occurs in fewer than 5 percent of cases, is
defined by the persistence of leukemic blasts in the blood, bone marrow, or any
extramedullary site after four to six weeks of induction therapy. Induction failure has
historically been considered a particularly ominous sign and an indication for allogeneic
HCT [61]. Due to the rarity of induction failure, information regarding this population has
been limited to small numbers of patients enrolled on prospective clinical trials [62-64].
An international retrospective analysis from 14 cooperative study groups identified 44,017

children (≤18 years) with previously untreated ALL diagnosed from 1985 to 2000 [65], of
which 1041 (2.4 percent) had induction failure. In this cohort, patients with induction failure
were more likely to have had at least one of the following unfavorable features at
presentation: male sex, older age (>6 years), high leukocyte count
(>100,000 cells/microL), T cell leukemia, central nervous system (CNS) involvement, or the
11q23 chromosomal rearrangement (associated with abnormalities of KMT2A [previously
called MLL]). These same unfavorable features, except for male sex and CNS involvement,
were also associated with reduced survival after induction failure. At a median follow-up of
8.3 years, the estimated overall survival (OS) at 10 years for patients with induction failure
who did not demonstrate t(9;22)(BCR-ABL1) was 32 percent. For the 624 patients with
genetic data available, patients could be stratified by karyotype with the following estimated
10-year OS:
●High hyperdiploid cytogenetics (n = 55) – 72 percent

●Normal karyotype (n = 159) – 36 percent
●Other chromosomal aberration (n = 250) – 30 percent
●11q23/KMT2A abnormality (n = 50) – 16 percent
These data highlight the heterogeneity of the induction-failure population and the need for
individualized treatment decisions. Although the estimated OS rate was similar among the
198 patients who underwent HCT (43 percent) and the 427 patients who received
chemotherapy alone (41 percent), the effect of HCT on survival appeared to differ greatly
according to karyotype risk subgroup. As an example, children younger than six years with
precursor B cell ALL without KMT2A rearrangement (ie, low-risk factors) appeared to have
higher survival rates when treated with chemotherapy alone rather than HCT (73 versus 59
percent). In contrast, older children and those with elevated white blood cells (WBC), T cell
ALL, and additional cytogenetic risk factors had higher survival rates with a matched related
donor HCT rather than chemotherapy alone (59 versus 35 percent). A similar study in
Europe showed that adolescents and young adults with T cell ALL also did better with
allogeneic HCT compared with chemotherapy alone (67 versus 42 percent) [66].
A subset analysis of induction failures in a large prospective clinical trial suggested that
overall survival for patients with induction failure had improved somewhat with aggressive
chemotherapy, with a four-year overall survival of 60 percent [67].
In another study of 774 children with ALL (including T cell ALL) from the United States, 23
had persistent leukemia after completion of induction therapy and were treated with
additional induction chemotherapy. Although 21 patients eventually achieved complete
remission, their five-year event-free survival (EFS) was only 16 percent (95% CI 0-31
percent) regardless of management regimen, compared with 82 percent (95% CI 79-86
percent) in the group that achieved remission within one month and 79 percent (95% CI 70-
87 percent) in those who had protracted hypoplasia [63].
In a French study of 1395 children with ALL, a multivariate analysis identified three groups
based upon their risk for induction failure [64]. The intermediate- and high-risk groups had a
7- and 28-fold increase risk of induction failure compared with the low-risk group. The low-
risk group (n = 1080) had precursor B cell ALL without the "Philadelphia" translocation,
t(9;22). The intermediate-risk group had T cell ALL with mediastinal involvement and the
high-risk group had either the "Philadelphia" translocation or T cell ALL without mediastinal
involvement. The groups were treated based upon Berlin-Frankfurt-Munster study (BFM)
protocols. Overall, 53 patients failed induction therapy. With salvage therapy, 43 patients
entered complete remission, 39 after one second-line course of chemotherapy and four who
required more than one course. Both the overall survival rate and the EFS for the 53
patients who failed induction therapy compared with those who responded to therapy were
markedly lower (30 and 27 percent versus 85 and 75 percent, respectively).
A subset of patients with Philadelphia chromosome negative (BCR/ABL1 negative) ALL

have a gene expression signature profile similar to that seen with BCR/ABL1 positive
disease. This "BCR/ABL1-like B cell ALL" is clinically more aggressive than
other BCR/ABL1 negative ALL and resistant to standard chemotherapy. Detailed genomic
analysis identified alternative mechanisms of activated kinase signalling in the majority
of BCR/ABL1-like B cell ALL that may be targeted with novel agents in the future.
(See "Cytogenetics and molecular genetics in acute lymphoblastic leukemia", section on
'BCR-ABL1-like B cell ALL'.)
CNS PREVENTIVE THERAPY — Leukemic involvement of the central nervous system

(CNS) at the time of diagnosis is an uncommon finding, occurring in fewer than 5 percent of
patients [68,69]. However, before the use of preventive CNS therapy, up to 80 percent of
children with ALL who were in complete bone marrow remission relapsed with "leukemic
meningitis" [70].
The routine use of preventive CNS therapy is a major therapeutic advance in the treatment
of childhood ALL. CNS treatment usually begins during the induction phase and continues
throughout the remainder of the treatment regimen. Craniospinal radiotherapy has been
replaced by intrathecal chemotherapy in several CNS preventive therapy protocols. Current
protocols contain either no CNS radiotherapy, or have a significantly reduced dose of 12 to
18 Gy. Outcome data from these protocols have demonstrated that replacement of
craniospinal radiotherapy with frequent administrations of intrathecal therapy does not
compromise event-free or overall survival [4,71-77].
Craniospinal radiotherapy or cranial radiotherapy, once considered the standard of care,

was effective in preventing CNS leukemia but was associated with significant toxicity, such
as cognitive impairment and decreases in white matter volume [78,79]. Approximately 50
percent of children treated with 24 Gy craniospinal radiation developed CNS changes
detected by magnetic resonance imaging (MRI) (atrophy, leukoencephalopathy,
calcifications, or grey matter abnormalities), secondary brain tumors, and had decreased
performance on neuropsychological testing [80,81]. As an example, a cancer survivorship
study of 102 adult survivors of ALL who received radiotherapy suggested that there is a
progressive decline in attention and verbal functioning that persists into adulthood [82]. The
long-term toxicities of cranial radiation are discussed in more detail separately.
(See "Overview of the outcome of acute lymphoblastic leukemia in children and
adolescents", section on 'CNS and cognition' and "Overview of the outcome of acute
lymphoblastic leukemia in children and adolescents", section on 'Brain
tumors' and "Delayed complications of cranial irradiation".)
The efficacy of intrathecal prophylaxis was illustrated in a randomized trial from the Dana-
Farber Cancer Institute ALL Consortium, in which children with standard-risk ALL were
assigned to receive either intensive triple intrathecal chemotherapy
(cytarabine/methotrexate/hydrocortisone) or 1800 cGy cranial radiation with less frequent
intrathecal therapy [71]. There was no difference between the two groups in five-year event-
free survival (EFS) (83 versus 86 percent) or the rate of CNS relapse (6 percent in each
group). A subsequent analysis of the neuropsychological outcomes found that cognitive
function was in the average range in both groups [72]. However, children who received 18
Gy or more of cranial radiotherapy had less fluent language output and were less effective
at modulating their behavior according to their parents.
A subsequent study evaluated the efficacy of regimens without cranial irradiation in 498
consecutive children (age range 1 to 18 years) with ALL who were treated with triple
intrathecal therapy and intensified systemic chemotherapy based upon disease risk
stratification after remission induction [4]. Intrathecal cytarabine was initially administered on
day 1 of remission induction and followed by subsequent triple intrathecal
chemotherapy (cytarabine/methotrexate/hydrocortisone). The number of intrathecal
treatments ranged from 13 to 25 and was based upon disease risk stratification and patient
characteristics, including CNS status of disease.
The following findings were noted:
●The five-year event-free and overall survival rates were 86 and 94 percent,
respectively.
●The five-year cumulative risk was 3.9 percent for any CNS relapse (isolated, and
combined CNS and hematologic relapse) and 2.7 percent for isolated CNS relapse.
●The five-year remission rate was significantly higher in the 71 patients who would
have previously received prophylactic cranial irradiation than 56 historical controls who
received cranial irradiation (91 versus 73 percent).
A similar study of 156 children from Taiwan indicated that triple intrathecal therapy could be
used to replace radiotherapy, suggesting that replacement of radiotherapy with more
intense intrathecal therapy can be generalized to a wide variety of ALL protocols [76].
The results of these studies demonstrate that intrathecal therapy provides similar event-free
and overall survival in a cohort of children with ALL. However, all recommendations for CNS
preventive therapies should be evaluated in the context of the related systemic therapy
regimens and should not be applied to other treatments without more evidence. Some
current protocols continue to incorporate lower dose cranial radiation (<1800 cGy) for
patients where CNS leukemia is felt to be a significant risk factor.
Although the incidence of neurotoxicity is reduced by intrathecal therapy, it is not eliminated

and remains a significant risk. Intrathecal chemotherapy (with either methotrexate alone, or
methotrexate combined with cytarabine and prednisone) is associated with acute
neurotoxicity [83], including seizures and leukoencephalopathy [83].
There is also an increasing body of evidence that CNS-directed therapy can impact
attention and cognitive function. These effects appear to be more significant in girls and
children who are radiated at a younger age. Because of the impact of these changes on
functioning into adulthood, broad strategies for educational and pharmacologic interventions
have been developed to remediate established cognitive dysfunction following childhood
ALL [84].
POST-REMISSION THERAPY — Consolidation or intensification therapy is the second

phase of ALL treatment and is initiated soon after attainment of complete remission (CR).
Ongoing treatment is required because small numbers of leukemic lymphoblasts remain in
the bone marrow despite histologic and molecular evidence of CR after induction therapy. In
such cases, relapse occurs quickly if therapy is not continued. The goal of post-induction
chemotherapy is to prevent leukemic regrowth, reduce residual tumor burden, and prevent
the emergence of drug-resistance in the remaining leukemic cells.
There is evidence that leukemias undergo a process known as clonal evolution [85]. During
induction, the vast numbers of leukemia cells originating from the dominant subclone are
eliminated. However, leukemia-initiating cells are often from a heterogeneous population at
diagnosis, with individual patients having multiple genetic subclones with leukemia-initiating
potential [86]. These subclones are present within a complex clonal architecture at
diagnosis, and often potentially chemoresistant leukemia-initiation cells are present but are
undetectable by minimal residual disease (MRD) assays. Post-induction therapies can help
prevent the emergence of a drug resistance by eliminating these subdominant clones that
were resistant to induction therapy. (See "Detection of minimal residual disease in acute
lymphoblastic leukemia" and "Clinical use of minimal residual disease detection in acute
lymphoblastic leukemia".)
Consolidation — Consolidation therapy usually lasts from four to eight months. It

commonly involves the use of several different drug combinations and drugs with
mechanisms of action that differ from those used during the induction phase. Regimens
often include the following drugs administered according to a variety of schedules to
maximize drug synergy and minimize the development of drug resistance [87,88]:
●Cytarabine
●Methotrexate
●Anthracyclines (daunorubicin, doxorubicin)
●Alkylating agents (cyclophosphamide, ifosfamide)
●Epipodophyllotoxins (etoposide, etopophosphamide)
Intensification of therapeutic regimens is based upon the patient's risk group classification
[89]. This has allowed a reduction of intensification therapy for patients with good prognosis
while providing more intensive treatment for those in the high-risk groups. End of induction
MRD, as well as cytogenetics and molecular abnormalities, are the most important
predictors of disease-free and overall survival [5,23,90]. Patients with detectable MRD have
an increased risk of relapse following conventional chemotherapy.
Ongoing trials are evaluating the escalation of consolidation therapy intensity for patients
who are MRD positive following induction, and the reduction of therapy intensity in MRD
negative cases. As an example, in one trial (UKALL 2003), 533 patients clinically identified
as having standard-risk or intermediate-risk ALL at diagnosis and MRD positivity (leukemia
cells >0.01 percent) in the bone marrow at the end of induction therapy were randomly
assigned to receive either standard or augmented post-remission therapy [91]. The
augmented therapy included additional doses of asparaginase, vincristine,
and methotrexate. Augmented therapy was associated with more adverse events including
hypersensitivity, pancreatitis, and mucositis/stomatitis. After a median follow-up of 70
months, augmented therapy resulted in superior five-year event-free survival (90 versus 83
percent; p = 0.04). However, overall survival was not statistically different between the
standard and augmented therapy groups (93 versus 89 percent, p = 0.16). Similar
strategies of therapy intensification for patients that are MRD positive after induction are
underway in Europe and the United States. (See "Clinical use of minimal residual disease
detection in acute lymphoblastic leukemia", section on 'MRD in children' and "Risk group
stratification and prognosis for acute lymphoblastic leukemia in children and adolescents",
section on 'Minimal residual disease'.)
Delayed intensification — Improved survival also has been gained with the addition of
more intensive therapy following consolidation, an approach known as delayed
intensification [92-94]. Delayed intensification involves the administration of a five- to eight-
week "pulse" of intensive, multi-agent chemotherapy similar to that administered during
induction and consolidation. Delayed intensification pulses were given either once [92,93] or
twice [95,96] during the first six months of post-remission therapy. Although the benefit of
two pulses of delayed intensification has not been demonstrated [5,97], the addition of a
single delayed intensification pulse has improved survival for both standard and high-risk
patients [96,98].
The intensity of delayed intensification therapy is commensurate with the patient's risk
grouping. As a general rule, the higher the risk for treatment failure, the more aggressive
intensification therapy is required. This was demonstrated in a Children's Oncology Group
trial of 1299 patients with higher risk ALL that had rapid marrow response to induction
therapy [99]. This study demonstrated that a more intensive delayed intensification regimen
resulted in improved event-free survival and overall survival at five years compared with
either standard therapy or longer duration of therapy.
During the delayed intensification phase of chemotherapy, most patients still have
significant myelosuppression and immunosuppression. They remain at risk for bacterial,
viral, and fungal infections during periods of neutropenia, and fevers should be aggressively
treated. Patients can also experience many of the same complications (eg, infection) seen
during induction therapy, although these are usually less common. (See 'Adverse
effects' above.)
More aggressive treatment regimens involving multiple chemotherapeutic agents place

high-risk patients at risk for additional complications. High-risk ALL patients have an
increased risk of secondary cancers (associated with epipodophyllotoxins or radiation) and
decreased fertility (a risk for adolescents receiving alkylating agents). (See "Overview of the
outcome of acute lymphoblastic leukemia in children and adolescents", section on 'Late
effects'.)
Allogeneic hematopoietic cell transplantation — Selected patients with high-risk disease

have an increased incidence of relapse during delayed intensification chemotherapy
[66,100,101]. This includes patients with severe hypodiploid ALL (less than 46
chromosomes), those with KMT2A rearrangements, and infants with ALL. With the
exception of patients <1 year of age, patients with these cytogenetic and molecular
abnormalities are candidates for allogeneic hematopoietic cell transplantation (HCT) during
first remission. There is evidence that HCT offers a survival advantage to those >10 years
of age with severe hypodiploidy (and without Li-Fraumeni syndrome), high-risk T cell ALL
[99], induction failure, and patients >1 year of age with 11q23 rearrangements [65,66].
An HLA-matched sibling donor is usually preferred and evidence shows that transplants
with an HLA-matched sibling donor are associated with fewer severe infections and
pulmonary complications [102]. A matched unrelated donor, however, is an acceptable
alternative when a sibling donor is not available and appears to result in similar clinical
outcomes (event-free survival, overall survival, non-relapse mortality, and relapse rates)
[102]. A partially matched family member donor or umbilical cord blood is a reasonable
option for patients who do not have an HLA-identical matched donor. (See "Donor selection
for hematopoietic cell transplantation".)
In contrast, HCT has been associated with increased mortality in infants [103]. There is
some evidence that HCT has been more successful in infants using reduced intensity
conditioning [104]. Further study is needed to determine if HCT can improve outcomes in
infants, particularly for those infants with KMT2A rearrangements. [65,66,99]
MAINTENANCE THERAPY — The overall treatment duration for most children with ALL is
30 to 42 months. After completion of the consolidation or intensification phase of therapy,
patients often receive a less intensive continuation regimen (eg, maintenance
chemotherapy) using daily oral 6-mercaptopurine (6-MP) [105], weekly methotrexate with
periodic vincristine, prednisone, and intrathecal therapy. 6-MP can be administered as a
tablet or as an oral suspension.
Children and families must be educated regarding the importance of maintenance therapy.
The importance of compliance with 6-MP was illustrated in a cohort study that demonstrated
an association between decreased adherence rates and an increased risk of relapse [106].
Better medication adherence is associated with a consistent daily routine for 6-MP ingestion
that integrates with the family's lifestyle (ie, selecting either morning or evening dosing) and
removing commonly practiced restrictions regarding coadministration of 6-MP with food or
milk products [107]. Self-reporting frequently overestimates the true intake of 6-MP,
particularly in nonadherent patients [108].
Although it is unclear whether all patients with ALL benefit from maintenance therapy that
includes a combination of pulse therapy vincristine and steroids in addition to a daily
regimen of 6-MP and weekly methotrexate, patients with standard-risk ALL who receive this
combination appear to have a more favorable long-term outcome than those treated with
only 6-MP and methotrexate [109]. The optimal time interval for vincristine plus steroid
pulses is also unclear; this question is currently being studied in a large prospective COG
trial. Patients with high-risk ALL, such as infants with ALL, may require a more aggressive
continuation regimen with additional drug combinations.
During maintenance therapy, patients remain at risk for infection. Fever in children who are
receiving chemotherapy must be evaluated and treated aggressively, especially if the
patient is either neutropenic or has a central venous access device. Trimethoprim-
sulfamethoxazole, dapsone, pentamidine, or atovaquone prophylaxis is continued to
prevent Pneumocystis pneumonia [110,111]. Therapy to prevent Pneumocystis infection
should be given during therapy and for at least three to six months following the completion
of treatment. Children and their household contacts should not be given live-virus
immunizations while the patient is receiving chemotherapy. (See 'Immunizations' below.)
PRIMARY CARE CONSIDERATIONS — For practical reasons, most patients with ALL
remain under the primary care of their oncologists during the induction and consolidation
portions of their chemotherapy. Once a patient enters the less intensive maintenance
therapy, however, the primary care provider (PCP) can often provide routine medical care
with scheduled visits to the oncologist for chemotherapy, particularly if the family lives some
distance from the oncology treatment center. When ALL therapy is complete, the PCP
resumes primary care for the patient, including visits for health maintenance and acute
illnesses.
During chemotherapy, the oncologist usually coordinates physical examinations,

procedures, and imaging studies. The PCP, however, plays an important role in
encouraging patients to return to their oncologist for scheduled visits and follow-up studies.
Encouragement to maintain regularly scheduled follow-up visits with their oncologist is
particularly important after the completion of chemotherapy treatment. Communication
between the PCP and the oncologist is critical throughout the treatment process.
The purpose of frequent follow-up visits after the cessation of chemotherapy is to examine
ALL survivors for disease recurrence and to screen them for the long-term side effects.
Patients are closely followed for several years after completion of chemotherapy. Although
there is no standard follow-up frequency, patients are typically seen by their oncologist
monthly for the first year after therapy completion and then at less frequent intervals for the
next two to four years. After three to five years, patients are followed on an annual basis
with a focus on long-term survivor issues. (See "Overview of the outcome of acute
lymphoblastic leukemia in children and adolescents", section on 'Late effects'.)
Immunizations — Experience with vaccine administration in children undergoing cancer

treatment is limited and there are few published data regarding response to specific
vaccines in patients receiving immunosuppressive chemotherapy. Data from HIV-infected
infants indicate that the risk of adverse events after immunization is low [112].
Patients with ALL should receive only inactive immunizations during chemotherapy [112].
Live-virus vaccines, such as MMR and oral poliovirus, are contraindicated. After completion
of chemotherapy, the patient should receive any missed vaccinations, including MMR and
varicella.
Cancer patients have a variable response to the immunizations received while

immunosuppressed. In addition, children with ALL whose immunizations were up-to-date at
the time of diagnosis may fail to maintain protective antibody titers after completion of
chemotherapy [113,114]. For this reason, it is recommended that antibody titers be checked
three to six months after the completion of chemotherapy, and that children be revaccinated
if they have low antibody titers [112,115]. (See "Immunizations in adults with cancer".)
Patients whose therapy included hematopoietic cell transplantation often repeat their
immunization series beginning approximately one year after transplantation. Testing of
immune function may provide evidence for safe immunization timing in these patients [112].
(See "Immunizations in hematopoietic cell transplant candidates and recipients".)
Varicella vaccine — Given the variability of chemotherapy regimens and the current
decreasing incidence of varicella, the American Academy of Pediatrics does not
recommend routine varicella vaccination for children actively receiving chemotherapy. If
varicella vaccination is performed in a child in remission without evidence of immunity, it
should be undertaken with expert guidance and with the availability of antiviral therapy
should complications occur [116]. After the completion of therapy, varicella titers should be
checked and, in the absence the varicella titers, the varicella vaccine should be
readministered.
Influenza vaccine — The annual influenza vaccine is recommended for children with ALL
receiving chemotherapy. It is also recommended that household contacts receive the flu
vaccine to prevent patient exposure during periods of neutropenia when the patient is
severely immunocompromised. Family members should not receive the nasal vaccine due
to concerns that this live virus could spread to the child with leukemia and result in severe
systemic disease in the immunocompromised host.
Monitoring for relapse — The signs and symptoms of ALL relapse typically are similar to
those of initial presentation. They include fever, malaise, bleeding, and bone pain.
(See "Overview of the presentation and diagnosis of acute lymphoblastic leukemia in
children and adolescents".)
ALL relapse most commonly occurs in the bone marrow and usually presents with
persistent peripheral blood cytopenias. Healthcare providers should pay close attention to
persistent abnormal blood counts in the ALL survivor. Monitoring for the presence of
minimal residual disease (MRD) is also common practice in patients who have had a stem
cell transplant as part of their treatment regimen. Prompt referral for bone marrow
examination is warranted if there is suppression of more than one cell line (white cells, red
cells, platelets) or unexplained suppression of one cell line that persists for longer than
three to four weeks. Prompt bone marrow examination is also warranted for patients with a
history of a stem cell transplant that have persistently positive MRD or recurrence of the
cytogenetic abnormality associated with their initial leukemia clone [117].
The second most common site of ALL relapse is the central nervous system (CNS).
However, the frequency of CNS relapse has diminished with the advent of initial
prophylactic intrathecal therapy. CNS relapse may manifest with symptoms of increased
intracranial pressure (headache, morning vomiting), nuchal rigidity, focal neurologic findings
(particularly cranial nerve palsies), or papilledema.
Testicular relapse is uncommon (<5 percent) with current treatment regimens. Testicular
relapse often presents as unilateral, painless testicular enlargement [118]. Diagnosis is
made by testicular biopsy. Bilateral biopsies are indicated if testicular relapse is suspected,
since leukemic cells are frequently found in the contralateral testis [118]. Leukemic
infiltrates rarely recur in other extramedullary sites, including the ovary, kidney, skin, and
eye.
RELAPSED DISEASE — Approximately 10 to 15 percent of children fail initial treatment of

ALL, but relapse rates are substantially higher (25 to 30 percent) in certain high-risk
subgroups [119].
Factors associated with an increased risk for relapse of ALL are discussed separately.
(See "Risk group stratification and prognosis for acute lymphoblastic leukemia in children
and adolescents".)
Management — Patients with relapsed ALL require aggressive reinduction therapy and
intensification, often using agents not administered in the original treatment protocol [120].
Patients with high-risk ALL, such as those with high initial white blood cell counts or children
>10 years old, often do not respond well to treatment with additional chemotherapy alone
[121,122]. Patients who have CNS or testicular relapse require radiation therapy at some
point during the rescue therapy program [123].
There is no consensus regarding optimal management of relapsed ALL, and we suggest

participation in a clinical trial whenever possible.
Various chemotherapy and immunotherapy approaches show promise in this setting, but
there are no prospective, randomized trials that have directly compared them. Retrospective
studies of relapsed ALL are difficult to compare because of heterogeneous populations of
patients.
Selection of therapy is influenced by characteristics of the relapsed leukemia (eg,

immunophenotype), available agents, and institutional and/or physician expertise. As
examples, some immunotherapeutic agents are available only in institutions with the
resources and expertise for their administration and management of treatment-related
complications.
The following agents have been used for the treatment of relapsed ALL (see "Treatment of
relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Remission
induction'):
T cell ALL — Treatment with activity for relapsed T-cell ALL includes:
●Nelarabine, a prodrug converted in vivo to ara-GTP, has shown efficacy as a single

agent for the treatment of relapsed or resistant T cell ALL in children and adults, and is
undergoing study for newly diagnosed T cell ALL by the Children’s Oncology Group
(COG). Indications for nelarabine treatment and toxicity are provided separately.
(See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults",
section on 'Nelarabine'.)
●Bortezomib is a proteasome inhibitor that prevents degradation of misfolded proteins,
and was shown to synergize with steroids in preclinical studies [124,125]. Bortezomib
has shown promise in the treatment of both pre-B ALL [126] and T cell ALL, and is
currently being tested in clinical trials for newly diagnosed T cell ALL by the COG.
Response rates of 68 to 73 percent were reported in very early relapse of B-ALL and in
T-ALL when combined with chemotherapy [126,127].
B cell ALL — Treatment options for relapsed B-cell ALL include:
●Blinatumomab is a bispecific T cell engager (BiTE) monoclonal antibody directed at

both CD19 on precursor B cell ALL tumor cells and CD3 on cytotoxic T cells. It is
approved by the US Food and Drug Administration (FDA) for children with relapsed B-
ALL. Its efficacy in relapsed ALL in children is not well defined but, in a phase 3 trial in
adults with relapsed or refractory B-ALL, blinatumomab was superior to chemotherapy
in regard to overall survival (OS), event-free survival (EFS), and complete remission
(CR) rate [128]. Blinatumomab is also effective in eradicating minimal residual disease
(MRD) in adults with relapsed pre-B ALL [129,130]. In children with relapsed
lymphoma, blinatumomab was associated with grade 3 neurologic toxicity (22 percent),
cytopenias and capillary leak syndrome [131]. (See "Treatment of relapsed or
refractory acute lymphoblastic leukemia in adults", section on 'Blinatumomab'.)
●Chimeric antigen receptor T (CAR-T) cells are a form of genetically modified
autologous immunotherapy that can be directed at B cell precursor ALL. This is a
customized treatment in which the individual's own T lymphocytes are genetically
modified (transfected) with a gene that encodes a chimeric antigen receptor to direct
the patient's T cells against the leukemic cells. The T cells are genetically modified ex
vivo, expanded in a production facility, and then infused back into the patient.
CAR-T therapy is associated with neurological events and cytokine release syndrome,
which is a systemic response (eg, high fever, flu-like symptoms, hypotension, mental
status changes) to the activation and proliferation of CAR-T cells. Facilities that
dispense these agents require special certification, staff must be trained to recognize
and manage its adverse events, and tocilizumab (a humanized monoclonal antibody
against the interleukin-6 receptor) must be available for immediate administration.
Tisagenlecleucel is a CD19-directed genetically modified autologous T cell
immunotherapy that is approved by the Food and Drug Administration (FDA) for
treatment of patients ≤25 years of age with B cell precursor ALL that is refractory or in
second or later relapse [132]. Tisagenlecleucel is only available in the United States
through a risk evaluation and mitigation strategy (REMS), and its label carries a boxed
warning for neurological events and for cytokine release syndrome. (See "Treatment of
relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Chimeric
antigen receptor T cells'.)
Studies of tisagenlecleucel for relapsed or refractory B cell precursor ALL in children
include:
•Ina single center study, a single infusion of tisagenlecleucel achieved 81 percent
CR, and all patients who had a response were found to be negative for MRD by
flow cytometry [133]. At six months, EFS and OS were 73 and 90 percent,
respectively, and the corresponding rates at 12 months were 50 and 76 percent.
Severe adverse events (grade 3/4) occurred in 73 percent.
•A multicenter trial of 63 pediatric and young adult patients reported an 83 percent
overall remission rate (including 63 percent CR and 19 percent CR with
incomplete hematologic recovery); all responding patients were negative for MRD
by flow cytometry [134].
Axicabtagene ciloleucel (axi-cel) is a CD19-directed CAR-T immunotherapy that has
been approved by the FDA for treatment of relapsed or refractory diffuse large B cell
lymphoma.
●Clofarabine is a deoxyadenosine analog that is approved by the US Food and Drug
Administration for treatment of pediatric patients (ages 1 to 21 years) with relapsed or
refractory ALL who have experienced treatment failure with two prior regimens. Studies
of clofarabine in adults with relapsed/refractory ALL are discussed separately.
(See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults",
section on 'Clofarabine'.)
Informative studies of clofarabine in children with relapsed/refractory ALL include:
•Ina multicenter study, 61 heavily pretreated children (median age, 12 years;
range 1 to 20) received a median of three cycles of clofarabine and achieved an
overall response rate of 30 percent (seven CR, five CR without platelet recovery,
six partial remissions) [135]. The most common severe adverse events (grade ≥3)
were febrile neutropenia, anorexia, hypotension, and nausea.
•Aretrospective multicenter study reported 61 percent overall response rate (52
percent CR) among children treated with clofarabine alone or combined with other
agents; half of the children were able to proceed to allogeneic HCT [136].
Clofarabine has been combined with other cytotoxic chemotherapy,
including etoposide, cyclophosphamide, and cytarabine, but such regimens have
resulted in a high rate of infections and other adverse events [137,138].
Patients who relapse after salvage chemotherapy or immunotherapy are candidates for
allogeneic HCT once they have attained second remission [139,140].
Survival after relapse — The outcome for patients with relapsed ALL is guarded when
compared with those without recurrence. Relapse following ALL therapy remains the
second most common cause of cancer-related death in children. The vast majority of
relapses occur within 2.5 years from diagnosis.
The survival rate of patients who relapse is dependent upon a variety of risk factors. This
was illustrated in a retrospective review of 1961 patients with a relapse from a cohort of
9585 enrolled children with ALL in the Children's Oncology Group clinical trials [141]. The
following findings were noted:
●The strongest predictor of survival was the time of relapse from initial diagnosis.
Patients who relapsed less than 18 months after diagnosis had a poor outcome, with a
five-year survival rate of approximately 21 percent.
●Five-year survival rates were higher in patients with isolated CNS relapse compared
with isolated or concurrent bone marrow relapse (59, 24, and 39 percent, respectively).
A similar study determined that patients with a late CNS relapse (greater than 18
months from diagnosis) fared better than those with a relapse prior to 18 months from
diagnosis (83 versus 46 percent) [142].
●Patients with high-risk disease had a lower survival rate than those with lower risk
disease. The lowest survival rate was in patients with high-risk disease who relapsed
before 18 months after diagnosis (15 percent).
●After adjusting for site and time of relapse, multivariate analysis of 1391 patients
demonstrated that older age (>10 years), presence of CNS disease at diagnosis, male
gender, and T cell disease were associated with lower survival rates.
As noted above, important predictors of survival include the site and timing of relapse and
the prior treatment regimen. These findings have been confirmed in other prospective
clinical trials [121,143,144].
●Genetic features – As with newly diagnosed disease, findings on routine

cytogenetics and FISH studies may help to stratify children with relapsed disease into
prognostic groups. As an example, in one study, the outcome of children with clinically
standard-risk relapsed B cell precursor ALL who had high-risk cytogenetic findings at
relapse was similar to that of children with clinically high-risk relapsed disease [145].
●Site of relapse – The long-term survival in ALL patients with bone marrow relapse
varies from 5 to 60 percent and depends upon the additional treatment for relapse,
standard versus high-risk initial disease status, and time to relapse [121,143]. Children
who have isolated CNS relapse fare better than those who have bone marrow relapse,
with five- to 10-year event-free survival rates of approximately 54 percent [141].
However, those with early CNS relapse (<36 months from diagnosis) tend to do less
well, with survival rates of only 38 percent [146].
●Time to relapse – The longer the duration between relapse and the time of
diagnosis, the better the survival rate [121,141]. Patients who relapse after completion
of chemotherapy fare better than those who relapse while still on therapy. Patients with
high-risk disease often relapse while still receiving chemotherapy. For these patients,
survival rates improve with increased duration of first remission. Patients with low-risk
disease tend to relapse after the completion of chemotherapy, often after a prolonged
time in remission.
Response to a second therapy regimen correlates directly with the length of first
remission [147,148]. As an example, in the experience of the Children's Oncology
Group, rates of survival after isolated bone marrow relapse were 21 percent for those
relapsing prior to 18 months from diagnosis versus 50 percent for those relapsing >36
months from diagnosis [141]. Although HCT appears to be more successful than
chemotherapy for patients who relapse early (ie, <36 months), its role in the
management of late failures is less well defined [139,149].
●Phase of treatment – Patients in the maintenance portion of their chemotherapy who
are receiving methotrexate and 6-mercaptopurine can be successfully treated with
more aggressive chemotherapy regimens. Patients who relapse while receiving
induction or consolidation chemotherapy, however, usually respond poorly to additional
chemotherapy. Following reinduction, these patients are often considered for HCT.
●Treatment regimen – Outcome also varies by the treatment regimen used at
relapse. As an example, a multicenter phase III randomized trial
compared idarubicin with mitoxantrone in 216 children with relapsed ALL [150].
Consolidation after this second induction was stratified based upon risk. Although
mitoxantrone did not result in an increase in complete remission (CR) rate after
induction, mitoxantrone resulted in significantly higher rates of progression-free (65
versus 36 percent), and overall (69 versus 45 percent) survival at three years.
The prognosis at the time of relapse, however, does not appear to be related to the intensity
of the initial therapy regimen used in current treatment protocols, or the age at
transplantation (ie, patients <14 years versus 14 to 18 years) [151,152]. As an example, a
report from the Children’s Oncology Group included 256 evaluable children with relapsed
ALL whose initial ALL treatment was randomly assigned to include either a standard
intensity postinduction regimen or an augmented intensity postinduction regimen [151].
Three-year survival rates after relapse were similar in the two treatment groups (36 versus
39 percent).

●Basics topic (see "Patient education: Leukemia in children (The Basics)")
SUMMARY
●Most children with newly diagnosed acute lymphoblastic leukemia (ALL) are treated
on research protocols with risk stratification based upon prognostic indicators available
at the time of presentation (table 1). Such research protocols have helped to
standardize treatment, improve survival rates, and reduce the long-term complications
of therapy.
●Although cure rates are >85 percent in many studies, significant challenges remain,
particularly for children with adverse prognostic factors. (See "Risk group stratification
and prognosis for acute lymphoblastic leukemia in children and adolescents".)
●Novel therapies for these patients and the implementation of new techniques to
further refine risk stratification should further improve survival rates in childhood ALL.
(See 'Induction therapy' above.)
●Because they are at risk for long-term complications, it is crucial that survivors of
childhood ALL continue regular follow-up with their oncologists after the cessation of
chemotherapy. Long-term complications are related to the type and intensity of the
treatment regimen. Patients with high-risk ALL receive more aggressive chemotherapy
and are at greater risk for acute and chronic adverse effects. (See "Overview of the
outcome of acute lymphoblastic leukemia in children and adolescents".)

Acute Lymphoblastic Leukemia

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Acute Lymphoblastic Leukemia

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INTRODUCTION — Acute leukemia, the most common form of cancer in children,

comprises approximately 30 percent of all childhood malignancies, with acute lymphoblastic

EPIDEMIOLOGY — As mentioned above, approximately 2500 to 3500 new cases of ALL

It appears the incidence of childhood leukemia is increasing as demonstrated by the two

However, in most cases, childhood ALL is not considered to be a familial disease. A

Hepatosplenomegaly — Hepatomegaly (64 percent) and/or splenomegaly (61 percent) are

Lymphadenopathy — Nearly half of children with ALL present with lymphadenopathy,

●Epitrochlear nodes are enlarged if they are >5 mm.

Lymphadenopathy associated with malignancy usually is nontender, firm, rubbery, and

Musculoskeletal pain — Although bone pain occurs commonly among children,

Testicular enlargement — Although rare, painless unilateral testicular enlargement can be

Peripheral blood abnormalities — Most children with ALL have

Morphology — In the World Health Organization classification system for hematologic

●Precursor B cell lymphoblastic leukemia/lymphoma, also called precursor B cell acute

Historically, childhood ALL was classified morphologically using the French-American-

The former FAB L3 category is currently described as Burkitt lymphoma/leukemia in the

Immunophenotype — Leukemia cells in ALL are classified according to immunophenotype

Approximately 70 to 80 percent of cases of childhood ALL are of B-precursor lineage (ie,

Cases of T cell ALL (ie, precursor T lymphoblastic leukemia), which comprise 15 to 17

●t(9;22) BCR/ABL1 translocation (Philadelphia chromosome) – Present in 3 to 4

The following abnormalities are associated with a favorable prognosis [60]:

●t(12;21) ETV6/RUNX1 (formerly referred to as TEL/AML1) rearrangement in B-

Several abnormalities, including hepatic dysfunction, coagulation abnormalities,

●Cytologic confirmation of the presence of leukemic cells in the cerebrospinal fluid

CNS involvement is often categorized into three groups:

●CNS1 – no blasts in the CSF

●Juvenile idiopathic arthritis (see appropriate topic reviews)

RISK GROUP STRATIFICATION/CLASSIFICATION — Current treatment protocols for

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education

●Basics topic (see "Patient education: Leukemia in children (The Basics)")

INTRODUCTION — In the World Health Organization classification system for hematologic

●Precursor B cell lymphoblastic leukemia/lymphoma, also called precursor B cell acute

●Clinically, a case is defined as lymphoma (LBL) if there is a mass lesion in the

The pathobiology, diagnosis, and clinical presentation of precursor B

CELL OF ORIGIN — Precursor B-lymphoblastic leukemia/lymphoma, also called precursor

EPIDEMIOLOGY — Precursor B-ALL/LBL accounts for approximately 2 percent of the

CLINICAL FEATURES — Precursor B-ALL/LBL more frequently presents in its leukemic

Histochemistry and immunophenotype — Evaluation often includes both histochemistry

Co-expression of myeloid antigens is seen in up to 30 percent of cases, most commonly

Genetic features — Rearrangement of antigen receptor genes is variable in lymphoblastic

Chromosomal abnormalities are common in precursor-B lymphoblastic neoplasms.

Numerical changes — Numerical changes in chromosomes include the following:

●Hyperdiploidy >50 chromosomes

Hyperdiploidy (51 to 65 chromosomes; DNA index 1.16-1.6) is seen in up to 50 percent of

Translocations — Many different translocations have been reported in B-ALL, three of

●The Philadelphia chromosome: t(9;22)(q34;q11); BCR/ABL1: historically associated

DIAGNOSIS — The diagnosis of precursor B-lymphoblastic leukemia/lymphoma is made

DIFFERENTIAL DIAGNOSIS — Precursor B cell LBL/ALL must be differentiated from other

The relationship between prognosis and cytogenetic abnormalities in ALL is discussed in

●Precursor B-lymphoblastic leukemia/lymphoma, also called precursor B cell acute

INTRODUCTION — In the World Health Organization classification system for hematologic

●Precursor B cell lymphoblastic leukemia/lymphoma, also called precursor B cell acute

●Clinically, a case is defined as lymphoma (LBL) if there is a mass lesion in the

CELL OF ORIGIN — Precursor T-lymphoblastic leukemia/lymphoma (precursor T-LBL),

EPIDEMIOLOGIC DATA — Precursor T cell LBL/ALL occurs most frequently in late

Immunophenotype and histochemistry — As in precursor B cell LBL/ALL, evaluation

Rare cases of LBL express antigens present on NK cells (CD16, CD57).

Genetic features — Rearrangement of antigen receptor genes is variable in lymphoblastic

A more detailed discussion of chromosomal abnormalities in ALL is presented separately.

DIAGNOSIS — The diagnosis of precursor T-lymphoblastic leukemia/lymphoma is made

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for precursor T

Indolent T-lymphoblastic proliferation is a nonmalignant entity that may mimic precursor T

PROGNOSTIC FACTORS — Prior to the development of aggressive ALL-type therapy, this

It also is increasingly appreciated that mutations in TP53 are found in 10 to 15 percent of T-