Blood and endocrine system diseases in children . Lesson 7. Topic: Leukemia and lymphomas
in children
Leukemia in
children:
- Acute Lymphoblastic Leukemia
Lymphoma in children
-
Non-Hodgkin's Lymphoma (NHL)
Leukemias,
the most common childhood cancers, account for about one third of pediatric
malignancies. Acute lymphoblastic leukemia (ALL) represents about 75% of all
cases in children and has a peak incidence at age 4 yr. Acute
myeloid leukemia (AML) accounts for about 20% of leukemias, with an incidence
that is stable from birth through age 10 and increases slightly during the
teenage years. Most of the remaining leukemias are of the chronic myeloid form;
chronic lymphoid leukemia rarely affects children. The overall annual incidence
of leukemia in white children is 43.7 per million population
and in black children, 24.3 per million children age 0 to 14 yr. The clinical
features of the leukemias are similar, because all involve severe disruption of
bone marrow function. Specific clinical and laboratory features differ,
however, and there is marked variability in responses to therapy and in
prognosis.
Childhood ALL was the first form of disseminated
cancer shown to be curable with chemotherapy and irradiation. ALL occurs
slightly more frequently in boys than girls. Reports of geographic clusters of childhood
leukemia have suggested some shared environmental factor. Some studies suggest
an in utero origin for leukemias presenting between 5 mo and 2 yr of age.
Investigations to date have not discovered the cause. Lymphoid leukemias occur
more often than expected in patients with Down and Bloom's syndromes and in
immunodeficiency diseases (e.g., congenital hypogammaglobulinemia,
ataxia-telangiectasia). Epstein-Barr virus has been implicated in the
pathogenesis of some cases of B-cell leukemia.
PATHOLOGY.
ALL is subclassified according to the morphologic,
immunologic, cytogenetic, and molecular genetic features of the leukemic cells.
Definitive diagnosis is generally based on examination of a bone marrow
aspirate. The cytologic appearance of the blast cells is so variable, even
within a single
specimen, that no
completely satisfactory morphologic classification has been devised. The
French-American-British (FAB) system distinguishes three morphologic subtypes,
L1 to L3. L1 lymphoblasts are predominantly small, with little cytoplasm; L2
cells are larger and pleomorphic with increased cytoplasm, irregular nuclear
shape, and prominent nucleoli; and L3 cells have finely stippled and
homogeneous nuclear chromatin, prominent nucleoli, and deep blue cytoplasm with
prominent vacuolation (Fig. 502-1) . Because of the essentially subjective
distinction between L1 and L2 blasts and a poor correlation with immunologic
and genetic findings, only the L3 subtype appears clinically meaningful.
Classification of ALL therefore depends on a
combination of cytologic, immunologic, and karyotypic features. Monoclonal
antibodies that recognize lineage-associated cell surface antigens can
determine the immunophenotype in most cases. The majority are
derived from B-progenitor cells; about 15% derive from T-progenitor cells, and
1% from relatively mature B cells. These immunophenotypes have both prognostic
and therapeutic implications. The subtypes of ALL and their relative incidences
are shown in Table 502-1 , along with certain clinical
characteristics. A minority of cases cannot be readily classified because they
demonstrate antigen expression associated with several different cell lineages
(i.e., mixed lineage or biphenotypic ALL).
Chromosomal abnormalities can be identified in at
least 80% of childhood ALL. The karyotypes of leukemic cells have diagnostic,
prognostic, and therapeutic significance. Further, they pinpoint sites for
molecular studies to detect genes that may be involved in leukemic
transformation and proliferation. Childhood ALL can also be classified by the
number of chromosomes per leukemic cell (ploidy) and by structural chromosomal
rearrangements such as translocations.
Another biologic marker with potential usefulness is
terminal deoxynucleotidyltransferase (TdT) activity, which is present in
B-progenitor-cell and T-cell ALL. Because this enzyme is absent in normal
lymphocytes, it can be useful in identifying leukemic cells in difficult
diagnostic situations. For example, TdT activity in cells from cerebrospinal
fluid (CSF) may help to distinguish early central nervous system (CNS) relapse
from aseptic meningitis.
Most patients with leukemia have disseminated
disease at diagnosis, with widespread bone marrow involvement and the presence
of leukemic blast cells in circulating blood. Spleen, liver, and lymph nodes
are usually involved. Hence, there is no anatomic staging system for ALL.
However, other features are used to assign children to groups with better and
worse prognosis.
CLINICAL MANIFESTATIONS.
About two thirds of children with ALL have had signs
and symptoms of their disease for less than 4 wk at the time of diagnosis. The
first symptoms are usually nonspecific and may include anorexia, irritability,
and lethargy. Patients may have a history of viral respiratory infection or
exanthem from which they have not appeared to recover fully. Progressive bone
marrow failure leads to pallor, bleeding, petechiae, and fever--the features
that usually prompt diagnostic studies (see Table 500-1)
.
On initial examination, most patients are pale, and
about 50% have petechiae or mucous membrane bleeding. About 25% have fever,
which may be falsely ascribed to an upper respiratory infection or otitis
media. Lymphadenopathy is occasionally prominent; splenomegaly is found in
about 60% of patients, whereas hepatomegaly is less common. About
25% of patients present with significant bone pain and arthralgias caused by
leukemic infiltration of the perichondral bone or joint or by leukemic
expansion of the marrow cavity. Rarely, signs of increased intracranial
pressure, such as headache and vomiting, indicate leukemic meningeal
involvement. Children with T-cell ALL are likely to be older and are more often
male; many have an anterior mediastinal mass, a feature that is strongly
associated with this subtype of the disease (see
Table 500-1) .
TABLE
502-1 -- Incidence of the Subtypes of Acute Lymphoblastic Leukemia in a Single
Study, with Incidence of Some Clinical Features at the Time of Diagnosis
|
Subtype |
No.
of Patients |
% |
Age
(Median) |
Leukocyte
Count ( × 103 ) (Median) |
%
Male |
%
with a Mediastinal Mass |
Associated
Chromosomal Abnormalities |
|
T
(T +) |
44 |
14 |
7.4
yr |
61.2 |
67.1 |
38.2 |
t(11;14) |
|
B
(slg +) |
2 |
0.6 |
|
|
|
|
t(8;14) |
|
PreB
(clg +) |
56 |
18 |
4.7
yr |
12.2 |
54.8 |
1.2 |
t(1;19) |
|
Early
preB (T-, slg -, clg-) |
209 |
67 |
4.4
yr |
12.4 |
56.5 |
1.0 |
t(9;22) |
|
Infant
early preB |
33 |
NA
|
<
1 yr |
50.0 |
55 |
None |
t(4;11) |
Adapted from Pullen JD,
Boyett JM, Crist WM, et al: Pediatric Oncology Group utilization of immunologic
markers in the designation of acute lymphoblastic leukemia subgroups. Influence on treatment response. Ann N Y Acad Sci
428:26, 1983.
TABLE 500-1 -- Common Manifestations of Childhood Malignancy
|
Sign/Symptom |
Nonmalignant Condition Mimicked |
Significance |
Example |
|
Hematologic |
|
|
|
|
Pallor, anemia |
Iron-deficiency anemia, blood
loss |
Bone marrow infiltration |
Leukemia, neuroblastoma |
|
Petechiae, thrombocytopenia |
Idiopathic thrombocytopenic
purpura |
Bone marrow infiltration |
Leukemia, neuroblastoma |
|
Fever, pharyngitis, neutropenia |
Streptococcal/viral pharyngitis |
Bone marrow infiltration |
Leukemia, neuroblastoma |
|
Systemic |
|
|
|
|
Bone pain, limp, arthralgia |
Osteomyelitis, rheumatologic
disease, trauma |
Primary bone tumor, metastasis to
bone |
Osteosarcoma, |
|
Fever of unknown origin, weight
loss, night sweats |
Collagen vascular disease,
chronic infection |
Lymphoreticular malignancy |
Hodgkin's disease, non-Hodgkin's
lymphoma |
|
Painless lymphadenopathy |
Epstein-Barr virus,
cytomegalovirus |
Lymphoreticular malignancy |
Leukemia, Hodgkin's disease,
non-Hodgkin's lymphoma, Burkitt's lymphoma |
|
Cutaneous lesion |
Abscess, trauma |
Primary or metastatic disease |
Neuroblastoma, leukemia,
histiocytosis X, melanoma |
|
Abdominal mass |
Organomegaly, hydronephrosis,
constipation |
Adrenal-renal tumor |
Neuroblastoma, Wilms' tumor,
hepatoblastoma |
|
Hypertension |
Renovascular disease, nephritis |
Sympathetic nervous system tumor |
Neuroblastoma, pheochromocytoma,
Wilms' tumor |
|
Diarrhea |
Inflammatory bowel disease |
Vasoactive intestinal polypeptide |
Neuroblastoma, ganglioneuroma |
|
Soft tissue mass |
Abscess |
Local or metastatic tumor |
Ewing's sarcoma, osteosarcoma,
neuroblastoma, rhabdomyosarcoma, eosinophilic granuloma, Askin's tumor |
|
Vaginal bleeding |
Foreign body, coagulopathy |
Uterine tumor |
Yolk sac tumor, rhabdomyosarcoma |
|
Emesis, visual disturbances,
ataxia, headache, papilledema |
Migraine |
Increased intracranial pressure |
Primary brain tumor; metastasis |
|
Chronic ear discharge |
Otitis media |
Middle or inner ear mass |
Rhabdomyosarcoma |
|
Ophthalmologic Signs |
|
|
|
|
Leukocoria |
Cataract, glaucoma |
White pupil |
Retinoblastoma |
|
Periorbital ecchymosis |
Trauma |
Metastasis |
Neuroblastoma |
|
Miosis, ptosis, heterochromia |
Third nerve paresis |
Horner's syndrome: compression of
cervical sympathetic nerves |
Neuroblastoma |
|
Opsoclonus/ataxia |
Drug reaction |
Neurotransmitters? Autoimmunity? |
Neuroblastoma |
|
Exophthalmos, proptosis |
Graves' disease |
Orbital tumor |
Rhabdomyosarcoma |
|
Thoracic Mass |
|
|
|
|
Anterior mediastinal |
Infection (tuberculosis),
lymphadenopathy, sarcoidosis |
Cough, stridor, pneumonia,
tracheal-bronchial compression |
Thymoma, teratoma, T-cell lymphoma,
thyroid |
|
Posterior mediastinal |
Esophageal disease |
Vertebral or nerve root
compression; dysphagia |
Neuroblastoma, neuroenteric cyst |
Modified from Behrman R, Kliegman R (eds):
Nelson Essentials of Pediatrics, 2nd ed.
DIAGNOSIS.
On initial examination, most patients have anemia,
although only about 25% have hemoglobin levels below 6 g/dL. Most patients also
have thrombocytopenia, but as many as 25% have platelet counts greater than
100,000/mm3 . About half of the patients have white blood cell (WBC) counts
less than 10,000/mm3 , and about 20% have counts greater than 50,000/mm3 . The
diagnosis of leukemia is suggested by the presence of blast cells on a
peripheral blood smear but is confirmed by examination of bone marrow, which is
usually completely replaced by leukemic lymphoblasts. The marrow occasionally
is initially hypocellular. Cytogenetic studies in these cases may be useful in
identifying specific abnormalities associated with preleukemic syndromes. If
the marrow cannot be aspirated or the specimen is hypocellular, bone marrow
biopsy provides the needed material for study. Cytogenetic studies can be
performed on biopsy specimens if they are placed in tissue culture medium.
In a bone marrow aspiration, a needle is used to suction out a small amount
of liquid bone marrow from the back of your hipbone. A bone marrow biopsy is
often taken at the same time. This second procedure removes a small piece of
bone tissue and the enclosed marrow.
A chest radiograph is necessary to search for a
mediastinal mass. Bone radiographs may show altered medullary trabeculae,
cortical defects, or subepiphyseal bone resorption. These findings lack
clinical or prognostic significance, and a skeletal survey is usually
unnecessary. CSF should be examined for leukemic cells, as early involvement of
the CNS has important prognostic and therapeutic implications. Uric acid level
and renal function should be determined before treatment is started.
DIFFERENTIAL
DIAGNOSIS.
The diagnosis of ALL is usually straightforward once
the possibility has been considered. Inclusion of ALL in the differential
diagnosis may be delayed if a child has been sick and febrile with adenopathy
for several weeks. The differential diagnosis includes bone marrow failure due
to aplastic anemia and myelofibrosis. Infectious mononucleosis produces a
somewhat similar clinical picture, but careful examination of the blood smear
should identify atypical lymphocytes. If doubt remains, a bone marrow aspirate
demonstrates a normal cell population. Some patients have unexplained fever and
joint pain that has been diagnosed as rheumatoid arthritis for months. Mature
lymphocytosis secondary to pertussis or benign lymphocytosis is easily
distinguished from ALL by morphology alone. Infiltration of the marrow by other
types of malignant cells (neuroblastoma, rhabdomyosarcoma,
TREATMENT.
Pharmacogenetic researchers have
discovered that a gene test can predict which children with acute lymphoblastic
leukemia will be cured by chemotherapy.
Contemporary treatment of ALL is based on clinical
risk, although there is no universal definition of risk groups. In general,
patients with a standard or average risk of relapse are between the ages of 1
and 10 yr, have a WBC count under 100,000/mm3 , lack evidence of a mediastinal
mass or CNS leukemia, and have a B-progenitor cell immunophenotype. The
presence of certain specific chromosomal translocations (as discussed later)
should be ruled out. The treatment program for standard-risk patients includes
administration of induction chemotherapy until the bone marrow no longer shows
morphologically identifiable leukemic cells, "prophylactic" treatment
of the CNS, and continuation chemotherapy. A sample treatment plan is outlined
in Table 502-2 .
A combination of prednisone, vincristine, and
asparaginase produces remission in about 98% of children with standard-risk ALL
within 4 wk. Fewer than 5% of patients require another 2 wk of induction
therapy. Consolidation and intensification phases of therapy using several
chemotherapeutic agents are often given after the induction of remission to
produce further rapid reduction in leukemic cell number and improve ultimate
outcome. Systemic continuation therapy includes the antimetabolites
methotrexate and 6-mercaptopurine plus vincristine and prednisone, which should
be given for 2 to 3 yr.
In the absence of prophylactic treatment, the CNS
was the initial site of relapse in more than 50% of patients. Leukemic cells
are usually present in the meninges at diagnosis even if they are not
identifiable in the CSF. These cells survive systemic chemotherapy because of
poor drug penetration of the blood-brain barrier. Cranial irradiation prevents
overt CNS leukemia in most patients but produces late neuropsychologic effects,
particularly in younger children. Therefore, standard-risk patients typically
receive intrathecal chemotherapy to prevent clinical CNS involvement.
Patients with T-cell ALL often suffer a relapse
within 3 to 4 yr if treated with a standard-risk regimen. With more intensive
multidrug regimens, 50% or more achieve long-term remission. One goal is to
develop targeted therapy that exploits the unique characteristics of leukemic T
cells. As an example of this approach, monoclonal antibodies to
T-cell-associated surface antigens can be conjugated to immunotoxins. The
antibody-immunotoxin complex would then attach to T lymphoblasts, undergo
endocytosis, and kill the cells.
B-cell cases with L3 morphology and surface
immunoglobulin expression have had a poor prognosis. These patients are now
best treated with short (3-6 mo) but very intensive regimens developed for
advanced B-cell lymphoma. With this approach, cure rates have improved
dramatically, from 20% a decade ago to over 70% or more.
TABLE 502-2 -- An Effective Treatment Regimen for Low-Risk Acute
Lymphoblastic Leukemia
Remission
Induction (4- 6 wk)
Vincristine
1.5 mg/m2 (max. 2 mg) IV/wk
Prednisone 40 mg/m2 (max. 60 mg) po/day
Asparaginase 10,000 U/m2 /day biweekly IM
Intrathecal
Treatment
Triple
therapy: MTX *
HC
*
Ara-C
*
Wkly × 6 during induction and then every 8 wk for 2 yr
Systemic
Continuation Treatment
6-MP
50 mg/m2 /day
MTX 20
mg/m2 /wk PO, IV, IM
Pulse
of MTX ± 6-MP given at higher doses
With
Reinforcement
Vincristine
1.5 mg/m2 (max. 2 mg) IV every 4 wks
Prednisone 40 mg/m2 /day
MTX =
methotrexate; HC = hydrocortisone; Ara-C = cytarabine; IV = intravenous;
|
Age* |
MTX |
HC |
Ara-C |
|
<1 yr |
10 mg |
10 mg |
20 mg |
|
2- 8 yr |
12.5 mg |
12.5 mg |
25 mg |
|
>9 yr |
15 mg |
16 mg |
30 mg |
* The dose of intrathecal medication is age
adjusted.
RELAPSE.
The bone marrow is the most common site of relapse,
although any site can be affected. In most centers, bone marrow is examined at
infrequent intervals to confirm continued remission. If bone marrow relapse is
detected, intensive retrieval therapy that includes drugs not used previously
may achieve cures in 15-20% of patients, especially those who have had a long
first remission (18 mo). For patients who experience bone marrow relapse during
treatment, intensive chemotherapy followed by bone marrow transplantation from
a matched sibling or related donor offers a better chance of cure. Autologous,
haploidentical, or matched unrelated donor transplants are options for those
without histocompatible sibling donors.
The most important extramedullary sites of relapse
are the CNS and the testes. The early manifestations of CNS leukemia are due to
increased intracranial pressure and include vomiting, headache, papilledema,
and lethargy. Chemical meningitis secondary to intrathecal therapy can produce
the same symptoms and must be considered in the differential diagnosis.
Convulsions and isolated cranial nerve palsies may occur with CNS leukemia or
as side effects of methotrexate or vincristine. Hypothalamic involvement is
rare but must be suspected in the presence of excessive weight gain or
behavioral disturbances. CSF pressure is usually elevated, and the fluid shows
a pleocytosis due to leukemic cells. If the cell count is normal, leukemic
cells may be identified in smears of CSF specimens after centrifugation (i.e.,
cytospin).
Patients with CNS relapse should be given
intrathecal chemotherapy weekly for 4 to 6 wk until lymphoblasts have
disappeared from the CSF. Doses should be age adjusted because CSF volume is
not proportional to body surface area (see Table 502-2)
. Cranial irradiation is the only treatment that completely eradicates overt
CNS leukemia and should be given after intrathecal therapy. Systemic treatment
should also be intensified, because these patients are at high risk of
subsequent bone marrow relapse. Finally, preventive CNS therapy should be
repeated in any patient whose disease has reoccurred in the bone marrow or in
any extramedullary site.
Testicular relapse generally produces painless swelling
of one or both testicles. Patients are often unaware of the abnormality,
mandating careful attention to testicular size at diagnosis and during
follow-up. The diagnosis is confirmed by biopsy. Treatment should include
irradiation of the gonads. Because a testicular relapse usually signals
impending bone marrow relapse, systemic therapy should be reinforced for
patients who are still on treatment or reinstituted for those who have a
relapse after treatment. CNS-directed therapy should also be repeated.
PROGNOSIS.
The overall cure rate for childhood ALL is estimated at about 80%. Thus,
parents can generally be assured at the time of diagnosis that the possibility
of cure is very good. Numerous clinical features have emerged as prognostic
indicators, only to lose their significance as treatment improves. For example,
immunophenotype is important in assigning risk-directed therapy, but its
prognostic significance has largely been eliminated by contemporary treatment
regimens. Hence, appropriate risk-directed treatment is the single most
important prognostic factor. The initial WBC count has a consistent inverse
linear relationship to the likelihood of cure. Age at diagnosis is also a
reliable predictor. Patients who are older than 10 yr and those younger than 12
mo and who have a chromosomal rearrangement involving the 11q23 region fare
much worse than children in the intermediate age group. Several other
chromosomal abnormalities influence treatment outcome. Hyperdiploidy with more
than 50 chromosomes is associated with a favorable outcome and responds well to
antimetabolite-based therapy. Two chromosomal translocations--the t(9;22), or
AML accounts
for 15-20% of the approximately 2,500 cases of pediatric leukemia diagnosed in
the
CLINICAL
MANIFESTATIONS.
AML may present with signs and symptoms related to
anemia, thrombocytopenia, or neutropenia (see Table 500-1)
. Children may present with fatigue and pallor or heart failure secondary to
anemia. Bruising, petechiae, epistaxis, or gum bleeding secondary to
thrombocytopenia may be presenting manifestations, as may fever secondary to
infection associated with neutropenia. Patients sometimes have hepatic or
splenic enlargement, lymphadenopathy, or gum hypertrophy. A localized mass of
leukemic cells, known as a chloroma, may herald the onset of AML. Orbital or
epidural locations are common sites of chloromas. At diagnosis, anemia and
thrombocytopenia are usually profound. The WBC may be normal, high, or low.
With extremely high WBC count (>100,000/mm3 ),
sludging of blood due to increased viscosity and stickiness of the WBCs may
occur, resulting in cerebrovascular symptoms (see Table
501-2) .
DIAGNOSIS.
The diagnosis of AML requires demonstration of
greater than 25% myeloblasts in the bone marrow. Characterization of the blasts
morphologically, immunophenotypically, and immunohistochemically distinguishes
ALL from AML. Within AML, the most commonly used classification system is the
FAB, which separates AML into seven subtypes according to morphologic
appearance and histochemical staining properties (Table
502-3). Certain karyotypic abnormalities are associated with specific
subtypes of AML. For example, t(15;17) is found in most cases of acute
promyelocytic leukemia (APL). APL is often associated with a life-threatening
form of disseminated intravascular coagulation at presentation owing to release
of procoagulant substances from the leukemic blast cells.
TABLE 502-3 -- Subtypes of Nonlymphoid Leukemia
|
Type |
FAB Classification |
|
Acute myeloid leukemia (AML) |
|
|
Myeloblastic, no maturation |
M0 and M1 |
|
Myeloblastic, some maturation |
M2 |
|
Hypergranular promyelocytic |
M3 |
|
Myelomonocytic |
M4 |
|
Monocytic |
M5 |
|
Erythroleukemia |
M6 |
|
Megakaryocytic |
M7 |
|
Chronic myelocytic leukemia (CML) |
|
|
Adult form |
|
|
Chronic phase |
|
|
Accelerated phase |
|
|
Blast crisis |
|
|
Juvenile myelomonocytic leukemia
(JMML) |
|
Inversion of chromosome 16 is often associated with
eosinophilia and the FAB M4 subtype.
Secondary leukemia is often associated with chromosomal
abnormalities, which affect 11q23 or with monosomy 7. Myelodysplastic syndrome,
which often evolves into AML, may have associated chromosomal changes such as
trisomy 8 or deletion of chromosome 5 or 7 (monosomy).
TREATMENT.
With aggressive initial induction regimens
containing an anthracycline and cytosine arabinoside with or without other
agents, remission can be achieved in 80% or more of patients. About 10% of
patients die early (i.e., during induction therapy) as a result of induction
failure, overwhelming infection, or hemorrhage. Vigorous supportive care with
broad-spectrum antibiotics, antifungals, blood products, and nutritional
support must be provided. Up to 6 wk or longer may be required to induce
remission and for the marrow to recover from the effects of chemotherapy.
During this time, most patients are critically ill. CNS prophylaxis with
intrathecal chemotherapy is also required to minimize the likelihood of CNS
relapse. After initial induction of remission, children who have an HLA-matched
related stem cell donor should undergo stem cell transplantation. Either bone
marrow or peripheral blood stem cells can be used. About 70% of patients who
can receive a matched sibling transplant are cured. Optimal therapy for
patients who do not have a matched donor is yet to be defined. The use of
interleukin 2 to produce immune modulation with an antileukemic effect is under
study during remission after completion of chemotherapy.
Patients with APL benefit from retinoic acid in
addition to chemotherapy including anthracycline. Such patients should not
receive marrow transplants in first remission. For reasons that are not
understood, children with Down syndrome and AML have a particularly good cure
rate (80%) with chemotherapy alone.
PROGNOSIS.
For patients with an HLA-matched family donor, the
cure rate is about 70% using chemotherapy followed by bone marrow
transplantation. For those without a suitable donor, chemotherapy alone cures
about 50%. Myelodysplastic syndrome or secondary AML does not usually respond
in a durable manner to chemotherapy. Children with AML who relapse have an
extremely poor prognosis. If they do not have an HLA identical donor, they
should be considered for alternative types of bone marrow transplantation such
as HLA-matched unrelated donor, cord blood transplants, or haploidentical
transplants, although such transplants are associated with a very high risk of
complications including infection and graft versus host disease.
Leucosis in children.
Background:
Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood,
representing nearly one third of all pediatric cancers. Annual incidence of ALL
is about 30 cases per million population, with a peak incidence in patients
aged 2-5 years. Although a small percentage of cases are associated with
inherited genetic syndromes, the cause of ALL remains largely unknown.
Many
environmental factors (eg, exposure to ionizing radiation and electromagnetic
fields and parental use of alcohol and tobacco) have been investigated as
potential risk factors, but none have been shown to definitively cause
lymphoblastic leukemia. Improvements in diagnosis and treatment have produced
cure rates that now exceed 70%.
Further
refinements in therapy, including the use of risk-adapted treatment protocols,
now attempt to improve cure rates for high-risk patients while limiting the
toxicity of therapy for low-risk patients. This article summarizes the advances
made in the diagnosis and treatment of childhood ALL.
Causes: Although a small
percentage of cases are associated with inherited genetic syndromes, the cause
of ALL remains largely unknown.
Pathophysiology:
In ALL, a lymphoid progenitor cell becomes genetically altered and subsequently
undergoes dysregulated proliferation and clonal expansion. In most cases, the
pathophysiology of transformed lymphoid cells reflects the altered expression
of genes whose products contribute to the normal development of B cells and T
cells. It has been long thought that leukemic blasts represent the clonal
expansion of hematopoietic progenitors blocked in differentiation at discrete
stages of development. Recent data challenge this theory and suggest that
leukemia arises from the stem cell that acquires features of differentiated
cells. While this may appear to be a subtle difference, it is important because
it implies the need to eradicate the leukemic stem cell, and not just the
differentiated blasts, to achieve a cure. Nevertheless, leukemic blasts provide
large uniform populations for molecular and functional analyses.
ALL generally is
thought to arise in the bone marrow, but leukemic blasts may be present
systemically at the time of presentation, including in the bone marrow, thymus,
liver, spleen, lymph nodes, testes, and the central nervous system (CNS).
Frequency: In
the
Race: ALL occurs more
frequently in whites than in blacks.
Sex: ALL occurs slightly
more frequently in males than in females. This difference is most pronounced
for T-cell ALL.
Age: The peak incidence of
ALL is in children aged 2-5 years.
CLINICAL
History: Children with
ALL generally present with signs and symptoms that reflect bone marrow
infiltration and extramedullary disease. Because the bone marrow is replaced
with leukemic blasts, patients present with signs of bone marrow failure,
including anemia, thrombocytopenia, and neutropenia. Clinically, the
manifestations include fatigue and pallor, petechiae and bleeding, and fever.
In addition, leukemic spread may be seen as lymphadenopathy and
hepatosplenomegaly. Other signs and symptoms of leukemia include weight loss,
bone pain, and dyspnea.
Physical: The physical
examination of children with ALL reflects bone marrow infiltration and
extramedullary disease. Patients present with pallor as a result of anemia,
petechiae, and bruising secondary to thrombocytopenia, and signs of infection
because of neutropenia. In addition, leukemic spread may be seen as
lymphadenopathy and hepatosplenomegaly.
Symptoms and
signs:
1. Intermittent fevers are common.
2. About 25% of patients experience of bone pain (in the pelvis, vertebral bodies, and legs).
3. Pallor, petechiae, and purpura.
4. Hepatomegaly or splenomegaly occurs in over than 60% of cases.
5. Lymphadenopathy is common, either localized or generalized to cervical, axillary, and inguinal regions.
6. The tests may be unilaterally or bilaterally enlarged secondary to leucemic infiltration.
7. Superior vena cava syndrome is caused by mediastinal adenopathy compressing the superior vena cava. A prominent venous pattern develops over the upper chest from collateral vein enlargement. The face may appear plethoric and the periorbital area may be edematous.
8. Tachypnea, orthopnea, and respiratory distress from a mediastinal mass may be apparent.
9. Leucemic infiltration of cranial nerves may cause cranial nerve palsies along with mild nuchal rigidity, nausea, vomiting, headache, irritability.
10. The optic fundi may show exudates or leucemic infiltration and hemorrhage from thrombocytopenia.
11. The cardiac examination often reveals a flow murmur and tachycardia due to anemia.
12. There may also be signs of infection.
ALL can be classified
broadly as either B- or T-lineage.
The diagnosis of
B-cell leukemia, which accounts for only about 3% of ALL cases, depends on the
detection of surface immunoglobulin on leukemic blasts. Prominent clinical
features include extramedullary lymphomatous masses in the abdomen or head and
neck and frequent involvement of the CNS.
T-cell ALL is
identified by the expression of T-cell-associated surface antigens, of which
cytoplasmic CD3 is specific. T-cell ALL cases can be classified as early-,
mid-, or late-thymocyte. The clinical features most closely associated with
T-cell ALL are high blood leukocyte counts and CNS involvement; a mediastinal
mass will be present in about half of the cases at the time of diagnosis.
Historically, the prognosis of patients with T-cell ALL has been worse than
that of patients with B-lineage ALL. With the use of intensive chemotherapy,
however, the outlook for patients with T-cell leukemia appears improved.
Differential Diagnosis
includes Acute Myelocytic Leukemia, chronic infections by Epstein-Barr virus
and cytomegalovirus (Mononucleosis), Idiopathic thrombocytopenic purpura (ITP),
transient erythroblastopenia of childhood, auto-immune hemolytic anemia,
aplastic anemia, juvenile rheumatoid arthritis.
Lab Studies:
1. A complete blood count is the most useful initial test, which reveals cytopenia: neutropenia, thrombocytopenia, or anemia. The white count is lower normal in 50% of patients (< 10,000 / ml), neutropenia (< 1,000 / ml) along with a small percentage of blasts amid normal lymphocytes. In 30%, the white count is between 10,000 and 50,000/ml and in 20% cases it is over 50,000/ml.
2. Most patients with ALL have decreased platelet counts (<150,000/ml) and decreased hemoglobin (<11g/dl).
3. Less than 1% has entirely normal CBC and blood smears.
4. Uric acid and lactate dehydrogenates are often elevated, serum phosphorus is occasionally elevated.
Cytogenetic
and molecular diagnosis
In more than 90%
of ALL cases, specific genetic alterations can be found in the leukemic blasts.
These alterations include changes in chromosome number (ploidy) and structure;
about half of all childhood ALL cases have recurrent translocations. Standard
cytogenetic analysis is an essential tool in the workup of all patients with
leukemia, because the karyotype of the leukemic cells has important diagnostic
and therapeutic implications. In addition, molecular techniques, including
reverse-transcriptase polymerase chain reaction (RT-PCR), Southern blot
analysis, and fluorescence in situ hybridization (FISH), have helped improve
diagnostic accuracy. Molecular analysis can identify translocations that are
not detected by routine analysis of karyotype and can distinguish lesions that
appear identical cytogenetically but differ at the molecular level.
Imaging Studies:
Imagine: chest X-ray may show mediastinal widening or an anterior mediastinal mass and tracheal compression; plain films of the long bones and spine may show demine realization, periosteal elevation, or compression of vertebral bodies.
Testicular
ultrasonography: Perform testicular
ultrasonography if the testes are enlarged on physical examination.
Renal
ultrasonography: abdominal ultrasound may show
kidney enlargement; Some clinicians prefer to evaluate for leukemic kidney
involvement to assess the risk of tumor lysis syndrome.
Obtain an
echocardiogram and ECG prior to the administration of anthracyclines.
Procedures:
A complete
morphologic, immunologic, and genetic examination of the bone marrow is
necessary to establish a diagnosis of ALL.
Bone marrow aspirate: this confirms the diagnosis of ALL. Bone marrow examination shows a homogenous infiltration of leucemic blasts replacing normal marrow elements.
In addition,
special stains (immunohistochemistry), immunophenotyping, cytogenetic analysis,
and molecular analysis all help classify each case.
Lumbar puncture with
cytospin morphologic analysis: This is performed before systemic chemotherapy
is administered to assess the presence of CNS involvement and to administer
intrathecal chemotherapy. Central nerves system leucemia, which is defined as a
cerebral spinal fluid white cell count ≥ 5/ml with blasts apparent on
cytocentrifuged specimen.
TREATMENT Because
leukemia is a systemic disease, therapy is primarily chemotherapy-based.
Different forms of ALL require different approaches for optimal results. For
example, B-cell ALL does not respond well to the chemotherapy traditionally
used for childhood ALL. However, outstanding results, with EFS estimates of
nearly 90%, have been obtained with treatments designed for Burkitt lymphoma,
which emphasize cyclophosphamide and the rapid rotation of antimetabolites in
high dosages. Thus, B-cell ALL was the first form of ALL to be recognized as a
distinct clinical entity on the basis of immunophenotypic and cytogenetic
features and the first to be treated by separate protocols designed
specifically for this leukemia's unique features.
Tumor lysis syndrome
Prior to and
during the initial induction phase of chemotherapy, patients may develop
tumor lysis syndrome. This syndrome refers to the metabolic derangements caused
by the systemic and rapid release of intracellular contents as the leukemic
blasts are destroyed by chemotherapy. Because some cells can die prior to
therapy, such derangements can occur even before therapy begins.
Primary
features of tumor lysis syndrome include
hyperuricemia (due to metabolism of purines), hyperphosphatemia, hypocalcemia,
and hyperkalemia. The hyperuricemia can lead to crystal formation with tubular
obstruction and, possibly, acute renal failure, requiring dialysis. Therefore,
electrolytes and uric acid should be monitored closely throughout initial
therapy.
To
prevent complications of tumor lysis syndrome,
all patients initially should receive IV fluids at twice maintenance rates,
usually without potassium. Sodium bicarbonate is added to the IV fluid to
achieve moderate alkalinization of the urine (pH 7.5-8) to enhance the
excretion of phosphate and uric acid. Avoid a higher urine pH to prevent
crystallization of hypoxanthine or calcium phosphate. Administer allopurinol to
prevent or correct hyperuricemia.
Bone marrow transplantation is rarely used because of the effectiveness of the chemotherapy alone. Patients whose blasts contain certain chromosomal abnormalities, such as t (9; 22) and t (4; 11) appear to have a better cure rate with early bone marrow transplantation. Bone marrow transplantation also is used in patients who have an early relapse of ALL.
Phases of therapy
With the
exception of B-cell ALL, the treatment of childhood ALL has 4 components,
including remission induction,
consolidation, continuation, and treatment of subclinical CNS leukemia.
Induction therapy generally consists of 3-4 drugs, which may include a glucocorticoid, vincristine, asparaginase, and an anthracycline. This type of therapy induces complete remission in more than 95% of patients.
Induction of remission: oral prednisone, intravenous vincristin and daunorubicin, intramuscular asparaginase, and intrathecal metotrexate. For T cell intravenous cyclophosphaneide has been given during induction.
Consolidation (ie, intensification) therapy is given soon after remission has been achieved in an attempt to
further reduce the leukemic cell burden before the emergence of drug
resistance. In this phase of therapy, the drugs are used at higher doses than
during induction, or different drugs are used, such as high-dose methotrexate
and 6-mercaptopurine, epipodophyllotoxins with cytarabine, or multiagent
combination therapy. Consolidation therapy, first used successfully in the
treatment of patients with high-risk disease, also appears to improve the
long-term survival of patients with standard-risk disease. Similarly, the
addition of intensive reinduction therapy (administered soon after remission
has been achieved) is beneficial for patients in both risk groups.
Consolidation is the second phase, during which intrathecal chemotherapy and sometimes cranial radiation therapy are given.
Duration
of therapy: Whereas B-cell ALL is treated with
a 2- to 8-month course of intensive therapy, achieving acceptable cure rates
for patients with B-precursor and T-cell ALL requires approximately 2-2.5 years
of continuation therapy. Attempts to reduce this time frame resulted in high
relapse rates after therapy was stopped. Most contemporary protocols include a
continuation phase based on weekly parenterally administered methotrexate given
with daily, orally administered 6-mercaptopurine, interrupted by monthly pulses
of vincristine and a glucocorticoid. Although these pulses have improved
outcome, they are associated with avascular necrosis of the bone. Patients with
high-risk ALL also may benefit from intensified continuation therapy that
includes the rotational use of drug pairs. The improvements in relapse-free
survival gained by intensification with anthracyclines or epipodophyllotoxins
must be weighed against the late sequelae of these agents, which include
cardiotoxicity and treatment-related acute myeloid leukemia.
Maintenance therapy includes daily oral mercaptopurine, weekly oral or intramuscular metotrexate and often, monthly pulses of intravenous vincristin and oral prednisone. Intrathecal chemotherapy, either with metotrexate alone or combined with cytarabine and hydrocortisone, is usually administered every 2-3 months. The duration of the treatment is between 2 ¼ and 3 ¼ years. “Pre-symptomatic” intrathecal chemotherapy is preventing CNS relapse.
CNS disease:
Treatment of subclinical CNS leukemia also is an essential component of ALL
therapy. Although cranial irradiation effectively prevents overt CNS relapse,
concern about subsequent neurotoxicity and brain tumors has led many
investigators to replace irradiation with intensive intrathecal and systemic
chemotherapy for most patients. This strategy has produced excellent results,
with CNS relapse rates of less than 2% in some studies. It is uncertain whether
cranial irradiation is necessary for patients with very high-risk ALL.
Supportive
care:
1. Hydration, alkalization of urine with intravenous sodium bicarbonate and oral allopurinol to prevent tumor lysis syndrome when treatment is started.
2. If hyperleucocytosis (>100,000/ml) is accompanied by hyperviscosity and mental status changes leukapheresis may be indicated.
3. Severe anemia can usually be corrected with a number of small red blood cell transfusions and intravenous furosemide.
4. Fever (t>38.3 ºC) and neutropenia require treatment with empiric broad-spectrum antibiotics.
5. Prophylaxis against Pneumocystic carinii by trimethoprim–sulfamethoxazole twice on the daily basis on 2 or 3 consecutive days weekly.
6. Varicella-zoster immune-globulin should be administered for patients, who are non-immune to varicella within 72 hours after exposure and treatment with intravenous acyclovir for active infection.
Surgical Care: Surgical care
generally is not required in the treatment of ALL, except for the placement of
a central venous catheter. Such catheters are used for the administration of
chemotherapy, blood products, and antibiotics, and for drawing blood samples.
Diet: Because of the use of
methotrexate, avoid folate supplementation.
MEDICATION
Drugs commonly
used during remission induction therapy include dexamethasone or prednisone,
vincristine, asparaginase, and daunorubicin. Consolidation therapy often
includes methotrexate and 6-mercaptopurine. Drugs used for intensification or
continuation include cytarabine, cyclophosphamide, etoposide, dexamethasone,
asparaginase, doxorubicin, methotrexate, 6-mercaptopurine, and vincristine.
Intrathecal chemotherapy includes methotrexate, hydrocortisone, and cytarabine.
Refer to specific protocol for duration of therapy with each drug and timing of
administration within each treatment cycle.
Drug Category: Antineoplastics
agents -- Cancer chemotherapy is based on an
understanding of tumor cell growth, and how drugs affect this growth. After
cells divide, they enter a period of growth (ie, phase G1), followed by DNA
synthesis (ie, phase S). The next phase is a premitotic phase (ie, G2), then
finally a mitotic cell division (ie, phase M).
Cell division
rate varies for different tumors. Most common cancers increase very slowly in
size compared to normal tissues, and the rate may decrease further in large
tumors. This difference allows normal cells to recover more quickly than malignant
ones from chemotherapy, and is the rationale behind current cyclic dosage
schedules.
Antineoplastic
agents interfere with cell reproduction. Some agents are cell cycle specific,
while others (eg, alkylating agents, anthracyclines, cisplatin) are not phase-specific.
Cellular apoptosis (ie, programmed cell death) also is a potential mechanism of
many antineoplastic agents. Drug Names:
Prednisone (Deltasone) -- A corticosteroid that is an important chemotherapeutic
agent in the treatment of ALL. Used in induction and reinduction therapy, and
also given as intermittent pulses during continuation therapy.
Adult Dose 20-25 mg
Pediatric Dose 40 mg/m2/d
Contraindications Documented hypersensitivity; serious infections (excluding meningitis
and septic shock) and fungal infections; varicella infections
Interactions May potentiate the thrombogenic effects of asparaginase; barbiturates,
phenytoin, and rifampin may decrease effectiveness
Precautions Gradual taper of dose required following prolonged treatment (ie, >2
wk); toxicity includes fluid retention, increased appetite, transient diabetes,
acne, striae, personality changes, peptic ulcer, immunosuppression,
osteoporosis, growth retardation; caution in diabetes, fungal infections, and osteonecrosis
Dexamethasone (Decadron, Dexone) --
A corticosteroid that is an important chemotherapeutic agent in the treatment
of ALL. Used in induction and reinduction therapy and also given as
intermittent pulses during continuation therapy.
Adult Dose 6-8 mg/m2/d
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; serious infections (excluding meningitis
and septic shock) and fungal infections; varicella infections
Interactions May potentiate the thrombogenic effects of asparaginase; barbiturates,
phenytoin, and rifampin may decrease effectiveness
Precautions Gradually taper following prolonged use; adverse effects include
gastritis, hypertension, hyperglycemia, salt and water retention, personality changes,
growth retardation, osteoporosis; caution with diabetes and osteonecrosis
Vincristine (Oncovin, Vincasar) --
Chemotherapeutic agent derived from periwinkle plant. Inhibits microtubule
formation in the mitotic spindle, causing metaphase arrest.
Adult Dose Induction
therapy: 2 mg IV qwk
Continuation therapy: 2 mg IV qmo
Pediatric Dose 1.5 mg/m2 IV; not to exceed 2 mg/dose
Contraindications Documented hypersensitivity; demyelinating form of Charcot-Marie-Tooth
syndrome; intrathecal administration
Interactions Acute pulmonary reaction may occur when taken concurrently with
mitomycin-C; asparaginase, CYP450 3A4 inhibitors (eg, itraconazole,
quinupristin/dalfopristin, sertraline, ritonavir), GM-CSF (eg, sargramostim,
filgrastim), or nifedipine increase toxicity; CYP450 3A4 inducers (eg,
carbamazepine, phenytoin, phenobarbital, rifampin) may decrease effects;
zidovudine increases risk of bone marrow suppression
Precautions Peripheral neuropathy manifested by constipation, ileus, ptosis, vocal
cord paralysis, jaw pain, abdominal pain, loss of deep tendon reflexes; reduce
dosage with severe peripheral neuropathy; bone marrow depression; local
ulceration with extravasation, SIADH
Asparaginase (Elspar, Kidrolase) --
Extracts of Escherichia coli or Erwinia L-asparaginase impair asparagine
synthesis and are lethal to cells that cannot synthesize the essential amino
acid asparagine.
Adult Dose Induction
therapy: 6,000-25,000 U/m2 IM 3 times/wk
Continuation therapy: Administer qwk
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; history of pancreatitis
Interactions Possible inhibition of methotrexate effect; possible increased toxicity
with vincristine or prednisone
Precautions Hypersensitivity reactions with local rash, hives, anaphylaxis; bone
marrow depression, hyperglycemia, hepatotoxicity, and bleeding may occur
Daunorubicin (Cerubidine) --
Anthracycline that intercalates with DNA and interferes with DNA synthesis.
Adult Dose 25 mg/m2 IV qwk during induction therapy
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; congestive heart failure, arrhythmias, or
cardiopathy
Interactions Coadministration of trastuzumab increases cardiotoxic effects
Precautions Myelosuppression and thrombocytopenia; may cause cardiac arrhythmias
immediately following administration and cardiomyopathy after long-term use;
nausea, vomiting, stomatitis, and alopecia; extravasation may occur, resulting
in severe tissue necrosis; caution with impaired hepatic, renal, or biliary
function
Methotrexate (Folex PFS) -- Folate
analogue that competitively inhibits dihydrofolate reductase, resulting in
inhibition of DNA, RNA, and protein synthesis.
Adult Dose 20-8000 mg/m2 PO/IV/IM qwk to qmo, depending on the protocol
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; alcoholism, hepatic insufficiency,
documented immunodeficiency syndromes, preexisting blood dyscrasias (eg, bone
marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia)
Interactions PO aminoglycosides may decrease absorption and blood levels of
concurrent PO methotrexate (MTX); charcoal lowers MTX levels; coadministration with
etretinate may increase hepatotoxicity of MTX; folic acid or its derivatives
contained in some vitamins may decrease response to MTX; coadministration with
NSAIDs may be fatal; indomethacin and phenylbutazone can increase MTX plasma
levels; may decrease phenytoin serum levels; probenecid, salicylates,
procarbazine, and sulfonamides, including TMP-SMZ, may increase effects and
toxicity of MTX; may increase plasma levels of thiopurines
Precautions Hematologic, renal, GI, pulmonary, and neurologic systems; discontinue
if significant drop in blood counts; aspirin, NSAIDs, or low-dose steroids may
be administered concomitantly with MTX (possibility of increased toxicity with
NSAIDs, including salicylates, has not been tested)
6-Mercaptopurine (Purinethol) --
Synthetic purine analogue that kills cells by incorporating into DNA as a false
base.
Adult Dose
50-75 mg/m2/dose PO qd
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity
Interactions Increased toxicity when administered with allopurinol; increased
hepatic toxicity when used in combination with doxorubicin
Precautions Renal or hepatic impairment; high risk of developing pancreatitis;
monitor for myelosuppression
Cytarabine (Cytosar-U) -- A
synthetic analogue of the nucleoside deoxycytidine. It undergoes
phosphorylation to ara-CTP, a competitive inhibitor of DNA polymerase.
Adult Dose Induction
therapy: 300-3000 mg/m2 IV qid
Continuation therapy: qmo or less
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; cerebellar toxicity
Interactions Decreased effects of gentamicin and flucytosine; increased toxicity
with other alkylating agents and radiation
Precautions Severe leukopenia and thrombocytopenia; immunosuppression, nausea, vomiting,
anorexia, stomatitis, GI ulceration, fever, alopecia, and rash; cerebellar
toxicity and ataxia also may develop
Etoposide (Toposar, VePesid) --
Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation
to arrest in the late S or early G2 portion of the cell cycle.
Adult Dose 300 mg/m2 IV, frequency depends on protocol; often not used at all
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; IT administration may cause death
Interactions May prolong effects of warfarin and increase clearance of methotrexate;
cyclosporine and etoposide have additive effects in cytotoxicity of tumor cells
Precautions Myelosuppression and development of secondary acute myeloid leukemia
Cyclophosphamide (Cytoxan) --
Chemically related to nitrogen mustards. As an alkylating agent, the mechanism
of action of the active metabolites may involve cross-linking of DNA, which may
interfere with growth of normal and neoplastic cells.
Adult Dose Induction
therapy: 300-1000 mg/m2 IV once
Continuation therapy: qmo or less
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; severely depressed bone marrow function
Interactions Possible increased
risk of bleeding or infection and enhanced myelosuppressive effects with
coadministration of allopurinol; may potentiate doxorubicin-induced
cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of
quinolones; chloramphenicol may increase half-life of cyclophosphamide while
decreasing metabolite concentrations; may increase effect of anticoagulants;
coadministration with high doses of phenobarbital may increase rate of
metabolism and leukopenic activity of cyclophosphamide; thiazide diuretics may
prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by
inhibiting cholinesterase activity
Precautions Alopecia, nausea, vomiting, stomatitis, diarrhea, myelosuppression,
immunosuppression, hemorrhagic cystitis, SIADH; also may cause sterility in
males
Drug Category: Antiemetics -- To
prevent chemotherapy-induced nausea and vomiting. Antineoplastic induced
vomiting is stimulated through the chemoreceptor trigger zone (CTZ), which then
stimulates the vomiting center (VC) in the brain. Increased activity of central
neurotransmitters, dopamine in CTZ or acetylcholine in VC appears to be a major
mediator for inducing vomiting. Following administration of antineoplastic
agents, serotonin (5-HT) is released from enterochromaffin cells in the GI
tract. With serotonin release and subsequent binding to 5-HT3-receptors, vagal
neurons are stimulated and transmit signals to the VC, resulting in nausea and
vomiting.
Antineoplastic agents may cause
nausea and vomiting so intolerable that patients may refuse further treatment.
Some antineoplastic agents are more emetogenic than others. Prophylaxis with
antiemetic agents before and following cancer treatment is often essential to
ensure administration of the entire chemotherapy regimen.
Ondansetron (Zofran) -- Selective
5-HT3-receptor antagonist that blocks serotonin both peripherally and
centrally. Prevents nausea and vomiting associated with emetogenic cancer
chemotherapy (eg, high-dose cisplatin) and complete body radiotherapy.
Adult Dose 8 mg PO/IV q8h for nausea
Pediatric Dose <3 years: Not established
3-11 years: 0.15 mg/kg PO/IV q8h
for nausea
>12 years: Administer as in
adults
Contraindications Documented hypersensitivity
Interactions Despite potential for CYP450 inducers (barbiturates, rifampin,
carbamazepine, and phenytoin) to change half-life and clearance of ondansetron,
dosage adjustment not usually required
Precautions Adverse effects include headache
Drug Category: Prophylactic
antimicrobials -- To prevent infection in patients receiving chemotherapy.
Sulfamethoxazole and trimethoprim (Cotrim, Septra, Bactrim) -- Inhibits bacterial growth by inhibiting
synthesis of dihydrofolic acid. All immunocompromised patients should be
treated with cotrimoxazole to prevent Pneumocystis pneumonia.
Adult Dose 2 tabs
Pediatric Dose 5-10 mg/kg/d (based on trimethoprim component)
Contraindications Documented hypersensitivity; megaloblastic anemia due to folate
deficiency
Interactions May increase PT when used with warfarin (perform coagulation tests and
adjust dose accordingly); most other interactions minor in severity when dosed
3 times/wk
Precautions Discontinue at first appearance of rash or sign of adverse reaction;
caution in folate deficiency; hemolysis may occur in individuals with G-6-PD
deficiency; patients with AIDS may not tolerate or respond to TMP-SMZ
Nystatin (Nilstat) -- Used for prevention of
fungal infections in patients with mucositis. Fungicidal and fungistatic
antibiotic obtained from Streptomyces noursei; effective against various yeasts
and yeastlike fungi. Changes permeability of fungal cell membrane after binding
to cell membrane sterols, causing cellular contents to leak.
Treatment should continue until 48
h after disappearance of symptoms. Drug is not absorbed significantly from GI
tract.
Adult Dose 10 mL
Pediatric Dose 5 mL
Contraindications Documented hypersensitivity
Interactions None reported
Precautions Not for treatment of systemic fungal infections
Clotrimazole troches (Mycelex) -- May be
used instead of nystatin for prevention of fungal infections. Broad-spectrum
antifungal agent that inhibits yeast growth by altering cell membrane
permeability, causing death of fungal cells.
Adult Dose 1 troche dissolved
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity
Interactions None reported
Precautions Not for treatment of systemic fungal infections; avoid contact with the
eyes; if irritation or sensitivity develops, discontinue use and institute
appropriate therapy
Itraconazole (Sporanox) -- Used for
prevention of fungal infections in high-risk patients. Fungistatic activity.
Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting
CYP450-dependent synthesis of ergosterol, a vital component of fungal cell
membranes. Bioavailability is greater for the oral solution than the capsules.
Adult Dose 200-400 mg
Pediatric Dose 10 mg/kg/d
Contraindications Documented hypersensitivity; coadministration with cisapride may cause
adverse cardiovascular effects (possibly death)
Interactions Inhibits CYP450 3A4; antacids may reduce absorption of itraconazole;
edema may occur with coadministration of calcium channel blockers (eg,
amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; may
increase tacrolimus and cyclosporine plasma concentrations when high doses are
used; rhabdomyolysis may occur with coadministration of HMG-CoA reductase
inhibitors (lovastatin or simvastatin); coadministration with cisapride can
cause cardiac rhythm abnormalities and death; may increase digoxin levels;
coadministration may increase plasma levels of CYP450 3A4 substrates (eg,
midazolam, triazolam, cyclosporine); phenytoin and rifampin may reduce
itraconazole levels (phenytoin metabolism may be altered)
Precautions Caution in hepatic insufficiencies
Complications: Complications of
leukemia and its therapy include the following:
Tumor lysis syndrome, Renal
failure, Sepsis, Bleeding, Thrombosis, Typhlitis, Neuropathy, Encephalopathy,
Seizures, Secondary malignancy, Short stature (if craniospinal radiation),
Growth hormone deficiency, Cognitive defects.
Prognosis: Overall, the cure rate
for childhood ALL is nearly 80%. However, the prognosis depends on clinical and
laboratory features described above. In general, the prognosis is best for
children aged 1-10 years. Adolescents have intermediate outcome, whereas
infants younger than 1 year have a poor outcome, with cure rates of about 30%.
Lymphoma
Lymphoma is the third most common cancer in children in the
Hodgkin's
disease accounts for about 5% of cancers in children and adolescents younger than
15 yr in the
Three
forms of Hodgkin's disease have been identified in epidemiologic studies: a
childhood form (14 yr old), a young adult form (15-34 yr old), and an older
adult form (55-74 yr old). The epidemiologic similarities of Hodgkin's disease
in young patients to paralytic polio in the 1940s and 1950s suggest an
infectious cause. The possible role of Epstein-Barr virus (EBV) is further
supported by serologic studies and the frequent presence of EBV genome in biopsy
material. Males predominate in patients younger than 10 yr at diagnosis, with
roughly equal gender incidence in adolescence. Pre-existing immunodeficiency,
either congenital or acquired, increases the risk of developing Hodgkin's
disease. A genetic predisposition or a common exposure to the same etiologic
agent could account for an apparent increased risk in twins and first-degree
relatives ranging from three to seven-fold.
PATHOLOGY.
The Reed-Sternberg cell, a
large (15 to 45 mum in diameter) cell with multiple or multilobulated nuclei,
is considered the hallmark of Hodgkin's disease, although similar cells are
seen in infectious mononucleosis, NHL, and other conditions. The cellular
origin of the Reed-Sternberg cell remains in dispute. An infiltrate of
apparently normal lymphocytes, plasma cells, and eosinophils surround the
Reed-Sternberg cell and vary with the histologic subtype. Other features that
distinguish the histologic subtypes include various degrees of fibrosis and the
presence of collagen bands, necrosis, or malignant reticular cells. The four
major histologic subtypes are lymphocyte predominant, nodular sclerosing, mixed
cellularity, and lymphocyte depleted. Historically, prognosis was linked to
histologic subtype, with lymphocyte predominant most favorable and lymphocyte
depleted least favorable. Since the advent of curative therapy, their
prognostic significance has diminished.
Hodgkin's disease appears to
arise in lymphoid tissue and spreads to adjacent lymph node areas in a
relatively orderly fashion. Hematogenous spread also occurs, leading to
involvement
of the liver, spleen, bone,
bone marrow, or brain, and is usually associated with systemic symptoms. Levels
of various cytokines have been shown to be elevated in patient sera or are produced
by cultured cell lines or Hodgkin's disease tissue. They may well be
responsible for the systemic symptoms of fever and night sweats (interleukin 1
or 2) and weight loss (tissue necrosis factor [TNF]).
Various degrees of cellular
immune impairment can be identified in the majority of newly diagnosed
Hodgkin's disease cases. The severity of the immune defect varies with the
extent of disease and persists even after successful curative therapy. Whether
it predisposes to the disease or results from it is unknown.
CLINICAL MANIFESTATIONS.
Painless,
firm, cervical or supraclavicular adenopathy is the most common presenting
sign. Inguinal or axillary adenopathy sites are uncommon areas of presentation.
An anterior mediastinal mass is often present and can disappear quickly with
therapy. Clinically detectable hepatosplenomegaly is rarely encountered.
Depending on the extent and location of nodal and extranodal disease, patients
might present with symptoms and signs of airway obstruction, pleural or pericardial
effusion, hepatocellular dysfunction, or bone marrow infiltration (anemia,
neutropenia, or thrombocytopenia). Nephrotic syndrome is a rare but recognized
presenting feature of Hodgkin's disease.
Systemic
symptoms considered important in staging are unexplained fever, weight loss, or
drenching night sweats (Table 503-1) . Less common and
not considered of prognostic significance are symptoms of pruritus, lethargy,
anorexia, or pain that worsens after ingestion of alcohol.
TABLE 503-1 --
|
Stage
I |
Involvement
of a single lymph node region or of a single extralymphatic organ or site |
|
Stage
II |
Involvement
of two or more lymphoid regions on the same side of the diaphragm; or
localized involvement of an extralymphatic organ or site and of one or more
lymph node regions on the same side of the diaphragm |
|
Stage
III |
Involvement
of lymph node regions on both sides of the diaphragm, which may be
accompanied by localized involvement of an extralymphatic organ or site or by
splenic involvement |
|
Stage
IV |
Diffuse
or disseminated involvement of one or more extralymphatic organs or tissues,
with or without associated lymph node enlargement |
* Stages are further categorized as A or B, based on the absence or
presence, respectively, of systemic symptoms of fever and/or weight loss.
Because of the impaired cellular
immunity, concomitant tuberculous or fungal infections may complicate Hodgkin's
disease and predispose to complications during immunosuppressive therapy.
Varicella-zoster infections occur at some time during the course of the disease
in about 30%.
DIAGNOSIS.
Any
patient with persistent, unexplained adenopathy unassociated with an obvious
underlying inflammatory or infectious process should have a chest radiograph to
identify the presence of a mediastinal mass before undergoing node biopsy.
Unless signs or symptoms dictate otherwise, additional laboratory studies can
be delayed until the biopsy results are available. Patients who have
persistently enlarged lymph nodes, even after serologically proven infectious
mononucleosis, should also be considered for biopsy.
Formal
excisional biopsy is preferred over needle biopsy to ensure that adequate
tissue is obtained, both for light microscopy and for appropriate
immunocytochemical studies, culture, and cytogenetic analysis if routine
studies fail to provide a firm diagnosis. Hodgkin's disease is rarely diagnosed
with certainty on frozen section. Ideally, a portion of the biopsy specimen
should be frozen and stored to allow for other studies.
Once
the diagnosis of Hodgkin's disease is established, extent of disease (i.e.,
stage) should be determined. Table 503-2 documents the
diagnostic work-up once the histologic diagnosis has been established. These
studies should provide all the information needed to clinically stage the disease
based on the
TABLE 503-2 -- Studies Necessary for Clinical Staging
of Hodgkin's Disease
|
Complete
blood count |
|
Erythrocyte
sedimentation rate, serum ferritin, serum copper |
|
Liver
function tests |
|
Chest
radiograph |
|
|
|
|
|
Gallium
scan |
|
Bone
marrow biopsy |
A complete
blood count (CBC) identifies abnormalities that might suggest marrow
involvement. Erythrocyte sedimentation rate (ESR), serum copper determination,
and serum ferritin levels are of some prognostic significance and, if abnormal
at diagnosis, serve as a baseline to evaluate the effects of treatment. Liver
function tests, though not particularly sensitive to the presence of liver
involvement, can influence treatment and treatment complications. A chest
radiograph is particularly important for measuring the size of the mediastinal
mass in relation to the maximal diameter of the thorax.
Surgical
staging is no longer routinely performed and should be considered only if
findings will significantly influence therapy. Bone marrow biopsy is necessary
in only those patients with advanced (stage III or IV) disease or with
"B" symptoms. Table 503-1 lists the separate lymph node regions as
they are applied to the staging process for Hodgkin's disease.
TREATMENT.
Because
of concern about late effects, treatment of children in
Early
Stage Disease (Stages I, II, and IIIA).
Cure
rates with radiation alone (3,500-4,500cGy) in surgically staged early stage
disease range from 40-80%, and the overwhelming majority of those who suffer
relapse can be salvaged with a combination of multiagent chemotherapy or
additional irradiation or both, resulting in cure rates of 90% or more.
Unfortunately, this approach produces growth retardation in skeletally immature
children and in some fully grown individuals and is associated with significant
long-term morbidity, including thyroid failure, cardiac and pulmonary dysfunction,
and an increased risk of breast cancer. For these reasons, many centers
treating children and adolescents used combined modality therapy or even
chemotherapy alone.
The
chemotherapy regimens in current use are based on MOPP * (nitrogen mustard [Mustargen],
vincristine [Oncovin], procarbazine, and prednisone), or ABVD * (doxorubicin
[Adriamycin], bleomycin, vinblastine, and dacarbazine), or combinations of the
two. As originally conceived, a minimum of six cycles of chemotherapy were
given with significant cumulative toxicity, including second malignancies,
sterility, and cardiac and pulmonary dysfunction. The long-term toxicity is
determined by the total dose of the offending agents. Newly developed programs
are aimed at reducing total drug doses and treatment duration and even
elimination of radiation therapy.
Advanced
Disease (Stages IIIB and IV).
Chemotherapy,
based on the same regimens as used in early stage disease, is considered the
primary treatment for patients with advanced disease. Because the cure rate
with conventional drug combinations, with or without radiation therapy, is only
60-70%, new and more aggressive regimens have been developed and are now in
clinical trials.
TREATMENT OF RELAPSE.
Patients
who suffer relapse after initial treatment with radiation alone, or after an
initial remission of at least 12 mo after chemotherapy alone or combined
modality therapy usually respond to additional chemotherapy or irradiation or
both. Those who never achieve remission or who suffer relapse after an initial
remission of less than 12 mo after chemotherapy or combined modality therapy
have a poorer prognosis and are candidates for myeloablative chemotherapy and
autologous stem cell or bone marrow transplant rescue.
PROGNOSIS.
Most
treatment programs result in disease-free survival rates of 60% or more, with
overall cure rates above 90% in those with early stage disease and exceeding
70% in more advanced cases. All newly diagnosed cases in children and
adolescents should be treated with curative intent; this is consistently and
effectively achieved with combined modality therapy. The choice of program is
then largely selected on the basis of observed or anticipated long-term
complications. Elimination of routine staging laparotomy and splenectomy avoids
concerns about surgical morbidity and postsplenectomy infections.
NHL results from malignant clonal
proliferation of lymphocytes of T-, or B-, or indeterminate cell origin. NHL
occurs with an annual incidence of 9.1 per million white and 4.6 per million
black children younger than 15 yr in the
PATHOLOGY AND PATHOGENESIS.
EBV
infection has a major role in the pathogenesis of Burkitt's lymphoma. The EBV genome
is present in tumor cells in 95% of "endemic" cases in equatorial
Africa compared to 20% in "sporadic" cases in the
Although
elaborate classifications of NHL have been developed, they have little
application to the pediatric disease. Most cases of NHL in children are
high-grade, diffuse neoplasms. Three histologic subtypes are recognized:
lymphoblastic (usually of T-cell origin), large cell (of T-, or B-, or
indeterminate cell origin), and small noncleaved cell lymphoma (SNCCL,
Burkitt's and non-Burkitt's subtypes, B-cell origin). The diagnosis and
classification of childhood NHL requires considerable hematopathologic
expertise and adequate diagnostic tissue, both fresh and frozen.
Chromosomal
translocation involving proto-oncogenes (e.g., tal1, rhomb2, rhombi, hox11,
lyl1, myc, lck) and T-cell receptor genes on chromosomes 7 or 14 results in
activation of the proto-oncogene, contributing to malignant transformation in
some cases of lymphoblastic lymphoma. In a subset of largecell lymphomas with
anaplastic histology, a t(2;5) results in rearrangement and fusion of the npm
gene on chromosome 5 with the ALK gene on chromosome 2, leading to formation of
a chimeric protein that may cause inappropriate phosphorylation of substrates
involved in cell growth and proliferation. In SNCCL, one of three chromosomal
translocations [i.e., t(8;14), t(8;22), t(2;8)] results in approximation of the
myc proto-oncogene on chromosome 8 to a regulatory region of either the kappa,
lambda, or mu chain genes, resulting in dysregulation of myc, thus contributing
to transformation.
CLINICAL MANIFESTATIONS.
Presenting
signs and symptoms vary with disease site and extent, and these in turn
correlate with histologic subtype.
Lymphoblastic
lymphoma often presents with intrathoracic tumor (usually a mediastinal mass)
and associated dyspnea, chest pain, dysphagia, pleural effusion, or superior
vena cava syndrome. Cervical or axillary adenopathy is present in up to 80% of
patients at diagnosis. Primary involvement of bone, bone marrow, testis, or
skin is not uncommon. The central nervous system (CNS) may also be involved.
SNCCL
presents as an abdominal tumor in 80% of
Large
cell lymphomas (LCL) occur in many sites, including the abdomen and
mediastinum. Extramedullary sites include skin, bone, and soft tissues. CNS
involvement is rare, in contrast to SNCCL and lymphoblastic NHL.
LABORATORY FINDINGS.
Laboratory
findings vary, depending on sites or organs involved. Elevated serum uric acid
levels and other features of tumor lysis syndrome often complicate the
presentation of SNCCL. Elevated serum level of lactate dehydrogenase is a
measure of tumor burden and may occur with any NHL subtype. A normal CBC does
not preclude marrow involvement. CT or MRI of the chest or abdomen or both provides
key information on disease extent. Surgical staging is not necessary.
DIAGNOSIS AND STAGING.
Prompt
tissue diagnosis and staging is important because of the rapid growth rate of
lymphomas, especially SNCCL. To ensure adequate tissue for accurate diagnosis
and subtyping, multiple needle biopsy specimens or a large wedge of tumor
should be obtained. Table 503-3 lists the studies
necessary to accurately stage the disease and provides baseline measurements of
organ function needed before treatment is instituted. In cases with airway
compromise and associated anesthesia risk and no easily accessible tissue to
sample, empirical therapy may be started.
The
St. Jude staging system defines tumor extent, which is important for treatment (Table 503-4) . Stage I applies to localized disease,
stage II regional (except for mediastinal tumors, which are designated stage
III), stage III extensive, and stage IV disseminated (CNS and/or bone marrow).
TABLE 503-3 -- Pretreatment Studies for Staging
Pediatric Non-Hodgkin's Lymphoma
|
Complete blood count |
|
Serum electrolytes, uric acid, lactate
dehydrogenase, creatinine, calcium, phosphorus |
|
Liver function tests |
|
Chest radiograph and chest CT if abnormal |
|
Abdominal and pelvic ultrasonography and/or CT scan |
|
Gallium scan and/or bone scan |
|
Bilateral bone marrow aspirate and biopsy |
|
Spinal fluid cytology |
TABLE 503-4 -- A Staging System for Non-Hodgkin's
Lymphoma in Childhood
|
Stage
I A
single tumor (extranodal) or single anatomic area (nodal), with the exclusion
of mediastinum or abdomen. |
|
Stage
II A
single tumor (extranodal) with regional node involvement. Two
or more nodal areas on the same side of the diaphragm. Two
single (extranodal) tumors with or without regional node involvement on the
same side of the diaphragm. A
primary gastrointestinal tract tumor, usually in the ileocecal area, with or
without involvement of associated mesenteric nodes only, which must be
grossly (>90%) resected. |
|
Stage
III Two
single tumors (extranodal) on opposite sides of the diaphragm. Two
or more nodal areas above and below the diaphragm. Any
primary intrathoracic tumor (mediastinal, pleural, thymic). Any
extensive primary intra-abdominal disease. |
|
Stage
IV Any
of the above, with initial involvement of central nervous system and/or bone
marrow at time of diagnosis. |
From Murphy SB: Classification,
staging, and end results of treatment of childhood non-Hodgkin's lymphomas: Dissimilarities
from lymphomas in adults. Semin Oncol 7:332, 1980.
TREATMENT AND PROGNOSIS.
Surgical
excision of localized intra-abdominal tumors often precedes the diagnosis of
NHL. In this and other situations, multiagent chemotherapy is the primary treatment.
Tumor lysis syndrome (ie., high serum potassium, uric acid, and high phosphorus
with low calcium levels) frequently complicates initial treatment of
disseminated disease. Appropriate hydration with addition of sodium bicarbonate
to produce dilute alkaline urine, administration of allopurinol, and correction
of electrolyte abnormalities are essential to minimize this life-threatening
complication.
NHL,
unlike Hodgkin's disease, is considered a disseminated disease from the time of
diagnosis. Even patients with limited stage disease require chemotherapy.
Patients with limited stage NHL, regardless of histologic subgroup, are
effectively treated with 6 cycles of CHOP (cyclophosphamide, vincristine,
methotrexate, and prednisone) or chemotherapy for three cycles, followed by 6
mo of mercaptopurine and methotrexate. About 90% are cured with this regimen.
Other effective regimens are available but appear to offer no advantage. The
emphasis now is on decreasing morbidity of therapy for these children while
maintaining the high cure rate.
TREATMENT OF ADVANCED NHL.
Patients
with advanced NHL are best treated with different therapy, depending on
histologic subtype.
Lymphoblastic.
The
chemotherapy regimens for nonlocalized lymphoblastic lymphoma are intensive, of
moderate duration, and include several chemotherapeutic agents given in cycles.
CNS therapy using cranial irradiation or intrathecal chemotherapy or both is
important for prevention of CNS disease. These intensive treatment programs are
continued for 15-18 mo.
SNCCL.
Relatively
short-duration (3-6 mo) intensive chemotherapy including an alkylating agent
coupled with other active agents produces survival rates of 70-80% in those
with disseminated disease. If relapse occurs, it becomes evident in the 1st yr
after diagnosis.
LCL.
Treatment
for patients with this rather heterogeneous group of tumors is controversial.
Intensive multiagent chemotherapy regimens similar to those used for
lymphoblastic lymphoma have produced long-term survival rates of 50-70%, as
have short, intensive regimens designed for Burkitt's NHL (used only for the
B-cell subset of large-cell cases). Event-free survival as high as 80% has been
reported for this subset. In
Pediatric Hodgkin Lymphoma
Hodgkin disease (Hodgkin's disease)
is a highly curable malignancy. Over the past few decades, the understanding
and insight into the biology of Hodgkin-Reed-Sternberg (HRS) cells as B-cell
derived have led to the classification of Hodgkin disease as a lymphoma or
Hodgkin lymphoma.[1]
Hodgkin lymphoma was the first cancer
to be cured with radiation therapy alone or with a combination of several chemotherapeutic
agents, even before understanding of the biology of Hodgkin lymphoma improved
(although its biology is still not fully understood). Since then, the cure rate
for children and adolescents with Hodgkin lymphoma has steadily improved,
particularly with the introduction of combined radiation and multiagent
chemotherapy.[2]
This therapeutic success has come at
the price of serious long-term toxicities, such that a 30-year survivor of Hodgkin
lymphoma is more likely to die of therapy-related complications than from
Hodgkin lymphoma. Therefore, the therapeutic paradigm has shifted toward
reducing treatment-associated toxicity while maintaining high cure rates. This
new paradigm has lead to the current risk-adapted, response-based approach to
the treatment of Hodgkin lymphoma
Pathophysiology
Hodgkin lymphoma is a germinal
center, B-cell malignant disorder that affects the reticuloendothelial and lymphatic
systems.[14] Disease
extension is predictable, is contagious, and can affect other organs and
systems. Organs that are predominantly affected include the lungs, bone, bone
marrow, liver parenchyma, and, rarely, the central nervous system.
Epidemiologic data suggest that
environmental, genetic, and immunologic factors are involved in the development
of Hodgkin lymphoma. Clustering of cases in families or racial groups supports
the idea of a genetic predisposition or a common environmental factor.
In identical twins of patients with
Hodgkin lymphoma, the risk of developing Hodgkin lymphoma is higher than that
of other first-degree relatives. Subjects with acquired or congenital
immunodeficiency disorders also have an increased risk of developing Hodgkin
lymphoma.
Findings from several epidemiologic
studies have suggested links between Hodgkin lymphoma and certain viral
illnesses. The strongest case to date is a relationship to Epstein-Barr virus
(EBV), in that EBV viral DNA can be found in HRS cells. Infants and children
aged 0-14 years with Hodgkin lymphoma have EBV DNA in their HRS cells more
often than young adults aged 15-39 years with Hodgkin lymphoma.
In addition, the prevalence of EBV-positive
classic Hodgkin lymphoma tumors differs geographically. The rate of EBV
positivity is 50% in Great Britain, Jordan, Egypt, and South Africa; 91% in
Greece; and 100% in Kenya. In general, EBV is most common in mixed-cellularity
Hodgkin lymphoma, in young children, and in developing countries.
In EBV-positive Hodgkin lymphoma,
EBV-encoding genes play a role in preventing apoptosis. Latent membrane
protein-1 (LMP-1) expressed in EBV-positive HRS cells mimics an activated CD40
receptor, activating the antiapoptotic nuclear factor–kappa-B (NF-κB)
pathway.
Advances in techniques to isolate HRS
cells, immunohistochemical and molecular biology techniques, have helped to
clearly identify 2 immunophenotypes for HRS cells. Immunophenotype I is
characterized by CD20 positivity, J-chain rearrangements, and, in general, CD30
and CD15 negativity, which is typical of nodular lymphocyte predominant Hodgkin
lymphoma. Immunophenotype II is characterized by CD30 positivity, absence of J
chains, and frequent expression of CD15, which is consistent with classic
Hodgkin lymphoma.[8]
The clinical manifestations of
Hodgkin lymphoma result from the mass effect that is mostly due to the reactive
tissue surrounding HRS cells, as well as cytokine production by HRS cells.
Systemic symptoms have been attributed to the production of interleukin (IL)–6,
whereas some of the histopathological characteristics, such as eosinophilia and
collagen sclerosis, have been attributed to cytokine production, such as IL-4,
IL-5 exotoxin, IL-6, IL-7, tumor necrosis factor (TNF), lymphotoxin,
transforming growth factor β (TGF-β), and basic fibroblast growth
factor.
A paracrine activation of NF-κB
in Hodgkin lymphoma is observed; both HRS cells and the surrounding supporting
cells produce cytokines that upregulate several members of the TNF receptor
superfamily, including CD30, CD40, or EBV latent membrane protein-1 (LMP-1).
The production of the ligand for
these receptors is responsible for the phosphorylation and translocation to the
nucleus of NF-κB. The constitutive translocation of NF-κB to the
nucleus of HRS cells is essential for the malignant transformation of HRS
cells. It leads to inhibition of apoptosis, proliferation, and secretion of
proinflammatory cytokines.[9]
Etiology
The etiology of Hodgkin lymphoma is
believed to be multifactorial, including the following:
·
Infectious agents
·
Genetic predisposition
·
Socioeconomic factors
·
Immune dysregulation
·
Environment
Several studies have documented a
link between Hodgkin lymphoma and EBV. EBV DNA can be identified in HRS cells
in approximately 50% of patients in the United States and in Western Europe and
in 90% or more of patients in developing countries.
Clustering in families suggests a
genetic predisposition, with an increased incidence especially among same-sex
siblings, monozygotic twins, and parent-child pairs. Familial Hodgkin lymphoma
has been associated with specific human leukocyte antigens (HLAs). Familial
cases account for 4.5% of all cases.
Socioeconomic factors in the United
States like parental income and parental education level are inversely related
to the incidence of Hodgkin lymphoma.
The increased susceptibility to
Hodgkin lymphoma in patients with T-cell immunodeficiency, human
immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome
(AIDS), or congenital immunodeficiency syndromes suggest a role for immune
dysregulation in the development of Hogdgkin lymphoma.
Clustering of cases in families or
racial groups supports the idea of a common environmental link. At present, no
conclusive association is recognized between dietary habits and the development
of Hodgkin lymphoma or other common environmental factos other than EBV
infection. Limited evidence suggests increased incidence in higher
socioeconomic status and smaller families.[15] This lends
support to the hypothesis that protection from early exposure to other children
may contribute to the development of Hodgkin lymphoma in high-income countries.
Epidemiology
The age-adjusted standardized rate
(ASR) of Hodgkin lymphoma in North America, western Europe, and Oceania is
usually just below 7 cases per million. For children and adolescents younger
than 15 years, the incidence is 5.5 cases per million. For individuals aged
15-20 years, the incidence is 12.1 cases per million. These rates are in
contrast to those in western Asia (from the Mediterranean to northwest India),
where the ASR is consistently higher than 7 cases per million.
Differences are observed among
countries with different levels of economic development, with highest
incidences among young children in developing countries. Over time, these
differences have become less pronounced.
In the United States and in Western
Europe, the childhood rate is lower than the young-adult rate. In Eastern
Europe, the young-adult rate is similar to that observed in the United States
and Western Europe, but the childhood rate is higher. Latin American countries
have patterns of incidence approaching those of the United States.
The incidence is relatively low in
Asia, with the exception of South Asia, where the incidence is relatively high.
Nodular sclerosis Hodgkin lymphoma is the most common type in developed
countries, whereas in some developing countries, mixed cellularity Hodgkin
lymphoma is the most common histologic type.
Race-,
sex-, and age-related differences in incidence
In the United States, the incidence
among whites and blacks is essentially the same. However, the ratio is 1.4:1 in
children older than 10 years.[4] A significant
male-to-female predominance of 3:1 is observed in children younger than 10
years. In older children and adults, the male-to-female ratio is about 1:1.
The incidences of Hodgkin lymphoma by
age show a bimodal distribution. In developed nations, the first peak occurs at
approximately age 20, and the second peak is observed in patients aged 55 years
or older. Hodgkin lymphoma is uncommon before age 5 years. However, in
developing countries, the first peak is shifted into childhood, usually before
adolescence.
Prognosis
In developed countries, the 5-year
overall survival (OS) for Hodgkin lymphoma of all stages is very high. Patients
with stage I or II disease have OS greater than 90%, whereas those with stage
II or IV disease have OS as low as 70%. Survival in developing countries may be
lower, depending on availability of care, medications, distance to the treating
centers, and number of patients who abandon therapy before completion.
Most acute and late complications are
due to treatment-related toxicities. Hypothyroidism after neck and chest
irradiation is prevalent and affects as many as 50% of patients who survive
pediatric Hodgkin lymphoma 10 years after treatment. In particular, white
female patients are at greater risk than male patients and black patients.
Cardiac and pulmonary complications
after radiotherapy depend on the cumulative doses of anthracyclines (cardiac
effects) and bleomycin (pulmonary effects) and on the radiation dose.
Girls and especially boys are at high
risk for infertility later in life after they receive regimens containing high
doses of alkylators. Therefore, male patients should receive counseling about
storing their sperm in a sperm bank, as appropriate, before such a regimen is
started.
As many as 30% of patients who
survive pediatric Hodgkin lymphoma develop a secondary malignancy 30 years
after their Hodgkin lymphoma is diagnosed. The most common secondary
malignancies are thyroid cancer, breast cancer, nonmelanoma skin cancer,
non-Hodgkin lymphoma, and acute leukemia.
Long-term survivors of Hodgkin
lymphoma are more likely to die from treatment-related complications 30 years
after diagnosis than from Hodgkin lymphoma.[10]
Patient Education
Before the initiation of treatment,
patients with Hodgkin lymphoma should be counseled about the potential
complications of Hodgkin lymphoma therapy. Depending on the therapeutic
modality, this may include the risk of cardiac disease, lung toxicity,
infertility, infection, and secondary cancers. All patients should be counseled
on health habits that may help reduce the risk of cancer and cardiovascular
disease, including avoidance of smoking, control of lipids, and the use of
sunscreen.
Patients should understand the risk
of psychosocial problems that may affect survivors of Hodgkin lymphoma.
Consultations with social workers, psychologists, and psychiatrists may be
helpful to manage some of these issues.
History
Most patients with Hodgkin lymphoma
present with persistent painless adenopathy, unresponsive to antibiotic
therapy. More than 70% of patients present with cervical lymphadenopathy.
Patients with mediastinal adenopathy may present with respiratory symptoms such
as shortness of breath, chest pain, or cough. These patients are at risk for
respiratory failure, especially if they undergo sedation or anesthesia for
diagnostic procedures. A large mediastinal mass may also cause superior vena
cava syndrome.
Patients with Hodgkin lymphoma may
present with symptoms that are associated with advanced disease and adverse
prognosis. The Ann Arbor staging system recognizes the following 3 symptoms,
known as B symptoms, as having prognostic significance (see Staging):
·
Unexplained fever with temperatures above
·
Unexplained weight loss of 10% or more in the previous 6
months
·
Drenching night sweats
Patients may have other symptoms that
relate to the cytokines produced by Hodgkin-Reed-Sternberg (HRS) cells or the
supporting environment within the affected lymph nodes, such as pruritus,
urticaria, and fatigue.
Several immune-mediated
paraneoplastic syndromes, such as immune thrombocytopenic purpura, autoimmune
hemolytic anemia, and nephritic syndrome can be associated with Hodgkin
lymphoma. These paraneoplastic syndromes can present before, after, or at the
time of presentation of Hodgkin lymphoma.
Physical Examination
Physical examination is important in
the evaluation of patients with Hodgkin lymphoma because it allows the
clinician to monitor the response to treatment. Careful evaluation of all lymph
node stations, hepatosplenomegaly, and involvement of Waldeyer or tonsillar
tissues should always be performed and the findings should be documented.
Patients may have firm, nontender
lymphadenopathy. This lymphadenopathy is cervical in 70-80% of patients and
axillary in 25%. Other sites are supraclavicular, inguinal, and, less often,
epitrochlear or popliteal. A mediastinal mass may cause superior vena cava
obstruction, respiratory symptoms, or both. Splenomegaly, hepatomegaly, or both
may be present.
Staging
After a tissue diagnosis is made, the
disease is staged by using imaging studies, evaluating the bone marrow
evaluation, and assessing for B symptoms.
The most widely used staging system
is the Ann Arbor staging system, as follows:
·
Stage I - Single lymph node region or single extranodal site
·
Stage II - Two or more lymph node regions on the same side of
the diaphragm
·
Stage III - Lymph node regions on both sides of the diaphragm
·
Stage IV - Diffuse or disseminated involvement of one or more
extralymphatic organs (liver, bone marrow, lung) or tissues with or without
associated lymph node involvement (The spleen is considered a nodal site.)
A or B designations are also used. B
includes the presence of at least one of the following symptoms:
·
Drenching night sweats
·
Unexplained fevers with temperature more than
·
More than 10% loss of body weight in the past 6 months
The A designation involves the
absence of symptoms described above. The E designation is extension or
contiguous involvement of extranodal sites by large mediastinal masses that are
not considered metastatic or stage IV.
Differential Diagnoses
·
Acute
Lymphoblastic Leukemia
·
Mononucleosis and
Epstein-Barr Virus Infection
Approach Considerations
Hematological and blood chemistry
evaluation may reveal nonspecific findings in patients with Hodgkin lymphoma
that may be associated with disease extent. Several of these findings have been
used as prognostic factors.
Chest radiography is used to assess
the bulk of the mediastinal mass, and CT, MRI, or ultrasonography of the neck, chest
or abdomen may be indicated for further assessment. Positron emission
tomography (PET) is used with increasing frequency to identify the extent of
disease at diagnosis and for follow up.
Lymph node biopsy findings may be
helpful. Bilateral bone marrow biopsy is necessary in all patients with
suspected involvement of the bone marrow and in those with stage IIB, III, or
IV disease. Staging laparotomy is no longer advocated in pediatric Hodgkin
lymphoma.
CBC, Chemistry Panel, and Other Tests
The complete blood cell count may
reveal the following:
·
Hemolytic anemia (Coombs positive), anemia of chronic
disease, or anemia secondary to involvement of the bone marrow
·
Leukocytosis, lymphopenia, eosinophilia, monocytosis
·
Thrombocytopenia due to marrow infiltration or idiopathic
thrombocytopenia purpura
Assessment of acute-phase reactants
may show elevations in the erythrocyte sedimentation rate (ESR) and C-reactive
protein, serum copper, and ferritin levels.
A full serum chemistry panel may aid
in evaluating levels of serum electrolytes; lactate dehydrogenase levels (LDH),
which reflects bulk of disease; alkaline phosphatase, which indicates bony
metastasis; as well as liver and kidney function.
In addition to stage and male sex,
the International Prognostic Factors for advanced Hodgkin lymphoma include
certain laboratory findings as poor prognostic factors. The following findings
may indicate a poor prognosis:
·
ESR of more than 50 mm/h
·
Hemoglobin concentration less than 10.5 g/dL
·
WBC count of 15,000/μL or less
·
Absolute lymphocyte count less than 800/μL
·
Albumin level less than 4 g/dL
Urinalysis may reveal proteinuria. Nephrotic
syndrome may be associated with Hodgkin lymphoma.
Radiography and Other Imaging Studies
Chest radiography is performed with
anteroposterior and lateral projections to assess the bulk of the mediastinal
mass. Mediastinal mass with a thoracic ratio of 33% or greater is of prognostic
importance.
CT or MRI of neck, chest, abdomen,
and/or pelvis are indicated to assess sites of disease (nodal and extranodal)
as well as to assess liver and spleen involvement. Ultrasonography can be used
to assess the abdominal and pelvic structures in centers with limited resources
in which CT scanning or MRI is not available. The minimal feasible amount of
ionizing radiation should be used for diagnostic imaging in order to limit the
future incidence of secondary malignancy.
Positron Emission Tomography
On PET scanning, uptake of the
radioactive glucose analog 2-[18F]fluoro-2-deoxy-D-glucose (FDG) is correlated
with proliferative activity in tumors undergoing anaerobic glycolysis. PET
scans are used with increasing frequency to identify the extent of disease at
diagnosis and for follow up. After 2 cycles of therapy with doxorubicin
(Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD), a positive PET
scan finding may be predictive of poor outcome. However, confirmation of its
utility with other regimens is pending.
PET scanning is becoming an important
modality to guide involved-field radiation therapy in adult Hodgkin lymphoma,[5] and its role
in guiding involved-field radiation therapy in pediatrics is being explored.
Gallium scanning is rarely used and
has been replaced by PET scanning. Bone scanning has been used when bony
metastases are suspected because of an elevated alkaline phosphatase level, but
the same information may be obtained with PET scanning.
Biopsy
Lymph node biopsy findings may be
helpful. Histopathologic studies consist of hematoxylin and eosin staining and
special immunohistochemical staining for surface markers such as CD15, CD20,
CD30, and CD45. Consider other immunohistochemical staining to ensure that they
are negative and to rule out non-Hodgkin lymphoma, such as CD3 and anaplastic
lymphoma kinase (ALK).
Clinicians must use care when
recommending diagnostic biopsies in patients with mediastinal lymphadenopathy.
Performing a diagnostic biopsy under local analgesia is preferable; if this is
not possible, these patients must be carefully evaluated by an
anesthesiologist. These patients may be difficult to intubate or, if intubated,
may be unable to be taken off respirator support.
Bilateral bone marrow biopsy is
necessary in all patients with suspected involvement of the bone marrow and in
those with advanced-stage disease.
Fine-needle aspiration is not
recommended because of lack of stromal tissue and the difficulty of classifying
Hodgkin lymphoma into one of the classic subtypes versus nodular
lymphocyte–predominant (NLP) subtype.
Histologic Findings
The most recent and currently
accepted classification is the Revised European-American Lymphoma (REAL)
classification as modified and adopted by the WHO. The REAL classification
distinguishes 5 classes of Hodgkin lymphoma, as follows[6] :
·
Nodular sclerosing
·
Mixed cellularity
·
Lymphocyte depleted
·
Lymphocyte rich
·
Nodular lymphocyte predominant (NLP)
The first 4 types are referred to as
classic Hodgkin lymphoma. Nodular lymphocyte predominant Hodgkin lymphoma is a
distinct entity with unique clinical features and a different treatment
approach. On immunophenotyping, the classic subtypes of Hodgkin lymphoma are
positive for CD15 and CD30 and may be positive for CD20, whereas NLP Hodgkin
lymphoma is negative for CD15 and CD30 but positive for CD20 and CD45.
Nodular sclerosing Hodgkin lymphoma
is notable for fibrous bands that result in a nodular pattern and lacunar-type
Hodgkin-Reed-Sternberg (HRS) cells wherein the cytoplasm in formalin-fixed
specimens retracts, forming a lacuna around the nucleus. This is the most
common type in all age groups (77% of adolescents and 72% of adults), although
it affects only 44% of younger children.
Mixed cellularity Hodgkin lymphoma
may have interstitial fibrosis, but fibrous bands are not observed. HRS cells
are classic in appearance or mononuclear. Lymphocytes may predominate in the
cellular background (see the image below). This subtype is more common in young
children (33%) than in adolescents (11%) or adults (17%).
Mixed cellularity Hodgkin lymphoma showing both mononucleate and
binucleate Reed-Sternberg cells in a background of inflammatory cells
(hematoxylin and eosin, original magnification X200).
Lymphocyte-rich Hodgkin lymphoma has
classic or lacunar-type HRS cells with rare or absent eosinophils on a cellular
background. This type is extremely rare.
Lymphocyte-depleted Hodgkin lymphoma
has large numbers of HRS cells with sarcomatous variants and a hypocellular background
because of fibrosis and necrosis. This type is also extremely rare.
NLP may be nodular, but fibrosis is
unusual. The HRS cell variants are known as lymphocytic and histiocytic
(L&H) or popcorn cells (because their nuclei resemble an exploded kernel of
corn). The nuclei are multilobed and vesicular with small nucleoli. The
characteristic halo of the classic H-RS cell is absent. The background consists
of histiocytes and lymphocytes with a B-cell predominance, in contrast to the
cellular background in classic Hodgkin lymphoma, which has a T-cell
predominance.
Approach Considerations
Hodgkin lymphoma is one of the most
curable malignancies of childhood and adolescence. Hodgkin lymphoma can be
cured with radiation therapy, chemotherapy, or a combination of both. However,
acute and late toxicities vary substantially according to the treatment
modality used. Therefore, most modern pediatric treatment strategies focus on
reducing late effects of therapy while maintaining excellent cure rates with
risk-adapted chemotherapy alone or response-adjusted combined-modality regimens.[7]
Placement of a peripheral or central
venous catheter for chemotherapy and supportive care is suggested but not
required. The decision to place a central venous catheter should be based on
the intensity of the treatment, the level of supportive care anticipated, the
state of the patient's peripheral venous access, and the patient's preference.
Staging laparotomy and splenectomy
are no longer routinely performed in patients with Hodgkin lymphoma. In
patients with suspicious lesions on imaging performed for staging, biopsy is
sometimes necessary if the findings might alter the treatment regimen.
Children with Hodgkin lymphoma should
be treated at a pediatric oncology center where pediatric oncologists,
radiation therapists, and full ancillary services are available for children
with malignancies. Initial evaluation, staging, and subsequent treatment of
Hodgkin lymphoma (Hodgkin's lymphoma) can be performed on an outpatient basis.
Admission is sometimes indicated for supportive medical care. Some clinical
trials that treat pediatric patients with Hodgkin lymphoma accept patient
enrollments well into the third decade of patient life.
Radiation Therapy
Radiation therapy was the first
curative modality used for Hodgkin lymphoma. However, the doses and fields used
for the treatment of adult Hodgkin lymphoma causes profound musculoskeletal
retardation, cardiac toxicity, and increased incidence of secondary malignancies
in the radiation field (eg, breast cancer in female survivors).
Currently, radiation is used as an
adjuvant treatment after chemotherapy. To reduce complications, risk-adapted or
response-based, low-dose, involved-field, or extended-field radiation is given.
In current trials, the use of nodal conformal radiation is being evaluated to
further decrease the burden of radiation to other tissues.
Positron emission tomography (PET)
scanning is becoming an important modality to guide involved-field radiation therapy
in adult Hodgkin lymphoma,[5] and its role
in guiding involved-field radiation therapy in pediatrics is being explored.
Chemotherapy Regimens
Chemotherapy alone is effective and
prevents radiation-associated treatment complications. This approach is
recommended especially in centers where pediatric radiation therapy is not
feasible but where chemotherapy can be reliably administered. However, in
pediatric oncology centers with well-developed pediatric radiation programs,
combined-modality therapy is preferred to avoid the high cumulative doses of
alkylating agents, bleomycin, and anthracyclines used in chemotherapy-only
protocols.
Although combined chemotherapy and
radiation broadens the spectrum of potential toxicities, the incidence and
severity of individual drug or radiation-related toxicities are generally
reduced because of the lowered doses of each component.
Regimens that contain alkylating
agents without anthracyclines include the following:
·
Mechlorethamine, vincristine, procarbazine, and prednisone
(MOPP)
·
Cyclophosphamide, vincristine, procarbazine, and prednisone
(COPP)
·
Cyclophosphamide, vincristine, methotrexate, and prednisone
(COMP)
·
Cyclophosphamide, vinblastine, procarbazine, and prednisone
(CVPP)
·
Chlorambucil, vinblastine, procarbazine, and prednisone
(ChVPP)
Regimens that contain anthracyclines
without alkylating agents include the following:
·
Adriamycin (doxorubicin), bleomycin, vinblastine, and
dacarbazine (ABVD)
·
Doxorubicin, bleomycin, vincristine, and etoposide (ABVE)
·
Vincristine (Oncovin), etoposide, prednisone, and doxorubicin
(Adriamycin) (OEPA)
·
Vincristine, doxorubicin (Adriamycin), methotrexate, and
prednisone (VAMP)
·
Vinblastine, bleomycin, etoposide, and prednisone (VBVP)
Regimens that contain alkylating
agents and anthracyclines include the following:
·
Adriamycin (doxorubicin), bleomycin, vincristine, etoposide,
prednisone, and cyclophosphamide (ABVE-PC)
·
Bleomycin, etoposide, doxorubicin (Adriamycin),
cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP)
·
Cyclophosphamide, vincristine, procarbazine, prednisone,
doxorubicin (Adriamycin), bleomycin, and vinblastine (COPP/ABV)
·
Vincristine, procarbazine, prednisone, and doxorubicin
(Adriamycin) (OPPA)
·
Doxorubicin (Adriamycin), vinblastine, nitrogen mustard,
vincristine, bleomycin, etoposide, and prednisone (Stanford V)
Other combinations of
chemotherapeutic agents, as well as novel therapies, have been studied and
found effective in front-line and salvage therapy for Hodgkin lymphoma.[11, 12]
Standard treatment regimens for
pediatric Hodgkin lymphoma are as follows:
Treatment
of Early or Favorable Disease
For early or favorable disease (stage
IA or IIA with < 3 nodal sites), standard treatment includes 2-4
chemotherapy cycles without alkylators (ie, VAMP; etoposide, bleomycin,
vinblastine, and prednisone [EBVP]; OEPA; or ABVE) plus low-dose,
involved-field radiation of 15-30 Gy or 6 chemotherapy cycles (alternating COPP
and ABVD or derivatives of these regimens) and no irradiation.
The use of very limited doses of
chemotherapy (2-3 cycles) should be administered only as part of a clinical
trial.
Treatment
of Intermediate-Stage Disease
For intermediate-risk disease (stage
IA, IIA, or IIA bulky disease with extension or ≥3 nodal sites), standard
treatment includes 4-6 chemotherapy cycles (ie, OPPA and COPP, Stanford V) plus
low-dose, involved-field radiation of 15-30 Gy or 6 chemotherapy cycles (alternating
COPP and ABVD or their derivatives).
Alternatively, a dose-intense, hybrid
regimen (eg, Stanford V, ABVE-PC, or BEACOPP) and no irradiation may be used.
Treatment
of Advanced or Unfavorable Disease
For advanced or unfavorable disease
(stages IIB, IIIB, or IV), one of the following 3 approaches is used:
·
6-8 chemotherapy cycles (OPPA and/or COPP, ABVE-PC, BEACOPP)
plus low-dose involved-field radiation of 15-30 Gy
·
Eliminating radiation therapy from the treatment of patients
in this category has reduced event-free survival.[13]
Supportive Medication
A variety of medications may be used
to counter the toxicities of treatment, such as the following:
·
Patients may benefit from antiemetics (eg, ondansetron,
diphenhydramine [Benadryl])
·
Pain relievers may include codeine and gabapentin (for
neuropathic pain secondary to vinca alkaloids)
·
To protect the gastric mucosa, patients receiving steroids
may be given H2-blockers or proton-pump inhibitors
·
Pneumocystis prophylaxis and granulocyte colony-stimulating
factor are also considered.
Long-Term Monitoring
Patients require regular monitoring
to assess their response to therapy and to check for adverse effects of
treatment. During periods of decreased blood cell counts due to bone marrow
suppressive effects of treatment, neutropenic and thrombocytopenic precautions
should be observed.
In patients who achieve remission,
follow-up visits are recommended every 2-4 months for the first 1-2 years and
every 3-6 months for the next 3-5 years. Most relapses occur in the first 3
years after therapy.
Medication Summary
Several chemotherapeutic agents in
various combinations are used to treat Hodgkin lymphoma (HL). The combinations
vary by the stage of disease and by the treating institution. In patients with
relapsing or unresponsive disease, autologous stem-cell transplantation
significantly prolongs disease-free survival. Various drug combinations have
been used with stem-cell rescue.
Although the intended target is the
malignant cells of Hodgkin lymphoma, the effects of chemotherapy on normal
cells of the body are considerable and account for the adverse effects observed
with these agents. Because most patients with Hodgkin lymphoma are long-term
survivors, one of the goals of current therapy is to decrease the long-term
adverse effects while maintaining excellent cure rates. The use of different
therapeutic agents with nonoverlapping toxicities is one way to achieve this
goal. Various combinations of the drugs presented below are used to treat
Hodgkin lymphoma.
Although adverse effects vary with
each drug, some are common to many drugs. These adverse effects include nausea,
vomiting, alopecia, bone marrow suppression, and, less commonly, secondary
malignancies.
Class
Summary
Cancer chemotherapy is based on an
understanding of tumor cell growth and of how drugs affect this growth. After
cells divide, they enter a period of growth (ie, phase G1), followed by DNA
synthesis (ie, phase S). The next phase is a premitotic phase (ie, G2), then
finally a mitotic cell division (ie, phase M).
Cell division rates vary for
different tumors. Most cancers grow quickly and undergo cell division more
often compared with normal tissues, and the growth rate may be decreased in
large tumors. This difference makes cancer more susceptible to chemotherapy.
Antineoplastic agents interfere with
cell reproduction. Some agents are specific to phases of the cell cycle,
whereas others (eg, alkylating agents, anthracyclines, cisplatin) are not.
Cellular apoptosis (ie, programmed cell death) is another potential mechanism
of many antineoplastic agents.
Mechlorethamine
(Mustargen)
This alkylating agent is a component
of the MOPP (mechlorethamine, vincristine, procarbazine, prednisone) regimen.
Bleomycin
Classified as antibiotic, bleomycin
induces free radical–mediated breaks in strands of DNA. This agent is part of
the ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine)
regimen.
Vinblastine
Vinblastine is a vinca alkaloid that
inhibits mitosis because of interactions with tubulin.
Dacarbazine
Dacarbazine is an alkylating agent
that inhibits DNA, RNA, and protein synthesis. It inhibits cell replication in
all phases of the cell cycle.
Etoposide
(Toposar)
Etoposide is an epipodophyllotoxin
that induces DNA strand breaks by disrupting topoisomerase II activity.
Vincristine
( Vincasar PFS)
Vincristine is a vinca alkaloid with
a mechanism of action similar to that of vinblastine.
Procarbazine
(Matulane)
Procarbazine is an alkylating agent
with mechanism of action similar to that of dacarbazine.
Prednisone
Prednisone is a corticosteroid used
to treat leukemias and lymphomas because of its lympholytic activity.
Cyclophosphamide
Cyclophosphamide is an alkylating
agent that is chemically related to nitrogen mustards. The mechanism of action
of its active metabolites may involve cross-linking of DNA, which may interfere
with growth of normal and neoplastic cells.
Methotrexate
(Rheumatrex, Trexall)
Methotrexate is an antimetabolite
that inhibits dihydrofolate reductase, which is necessary for conversion of
folate to biologically active tetrahydrofolate.
Doxorubicin
(Adriamycin)
An anthracycline that functions as a
DNA intercalator, doxorubicin inhibits topoisomerase II and produces free
radicals, which may destroy DNA. The combination of these 2 events can inhibit
the growth of neoplastic cells.
Antineoplastics, Antimetabolite
Class
Summary
These agents inhibit cell growth and
proliferation.
Gemcitabine
(Gemzar)
Cytidine analog. Metabolized
intracellularly to active nucleotide. Inhibits ribonucleotide reductase and
competes with deoxycytidine triphosphate for incorporation into DNA. Cell-cycle
specific for S phase. Inhibits DNA synthesis by inhibiting DNA polymerase.
Antineoplastics, Monoclonal Antibody
Class
Summary
The agents in this class target
specific antigens in carcinoma cells and induce cytotoxicity.
Brentuximab
vedotin (Adcetris)
Antibody genetically engineered
antibody drug conjugate directed at DC30 consisting of a CD30-specific chimeric
IgG1 antibody cAC10, a microtubule-disrupting agent, and a protease-cleavable
dipeptide that conjugates MMAE to cAC10. The antibody internalizes MMAE within
the cells, which then disrupts the microtubule network, causing cell cycle
arrest and apoptosis.
LITERATURE:
1.
Nelson Textbook of Pediatrics,
16e edition, P. 497-515.
2.
Bhatia S, Robison LL, Oberlin O, et al: Breast
cancer and other second neoplasms after childhood Hodgkin's disease. N Engl J
Med 334:745, 1996.
3.
Hudson MM, Donalson SS:
Hodgkin's disease. In: Pizzo PA, Poplack DG (eds): Principles and Practice of
Pediatric Oncology.
4.
Hudson MM, Donaldson SS:
Hodgkin's disease. Pediatr Clin North Am 44:891, 1997.
5.
Hudson MM, Pratt CB: Risk of
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Oncol Clin North Am 2:319, 1993.
6.
Schwartz RS: Hodgkin's
disease--time for a change. N Engl J Med 337:495, 1997.
7.
Liebowitz D: Epstein-Barr
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patients. N Engl J Med 338:1413, 1998.
8.
Link MP, Shuster JJ, Donaldson
SS, et al: Treatment of children and young adults with early-stage
non-Hodgkin's lymphoma. N Engl J Med 331:1259, 1997.
9.
Reiter A, Schrappe M,
Parwaresch R, et al: Non-Hodgkin's lymphomas of childhood and adolescence:
Results of a treatment stratified for biologic subtypes and stage-A report of
the Berlin-Frankfurt-Munster group. J Clin Oncol 13:359, 1995.
10.Sandlund
JT, Downing JR, Crist WM: Non-Hodgin's lymphoma in childhood. N Engl J Med
334:1238, 1996.
11.Shad
A, Magrath I: Non-Hodgkin's lymphoma. Pediatr Clin North Am 44:863, 1997.
12.Tugergen
DG, Krailo MD, Meadows AT, et al: Comparison of treatment regimens for
pediatric lymphoblastic non-Hodgkin's lymphoma: A children's cancer group study.
J Clin Oncol 13:1368, 1995.
13.Webb
A, Cunningham D, Cotter F, et al: BCL-2 antisense therapy in patients with
non-Hodgkin lymphoma. Lancet 349:1137, 1997.