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Case Presentation pediatric Non Hodgkin Lymphoma

History
The presentation of patients with non-Hodgkin lymphoma is acute or subacute, in contrast to
the indolent course that characterizes most lymphomas in adults.
The duration of symptoms before diagnosis is generally 1 month or less, with specific
complaints varying according to the predominant sites of involvement.
Bone marrow involvement in non-Hodgkin lymphoma may cause generalized or migratory
bone pain, but clinically significant cytopenias are uncommon, with their presence suggesting
a diagnosis of acute leukemia.
Symptoms of localized disease
Localized disease can manifest as lymphadenopathy (usually with firmness and no tenderness),
tonsillar hypertrophy, or a mass in virtually any location. In children, however, non-Hodgkin
lymphoma is primarily an extranodal disease.

Patients with supradiaphragmatic disease (eg, lymphoblastic lymphoma) often report having a
nonproductive cough, dyspnea, chest pain, and dysphagia.
Abdominal tumors (usually small noncleaved cell lymphoma [SNCCL] or B-cell large cell
lymphoma [LCL]) are associated with abdominal pain, constipation, masses, or ascites. An
acute abdomen occasionally is observed and may be mistaken for appendicitis. Rare primary
non-Hodgkin lymphoma of the pancreas presents with the clinical picture of pancreatitis. [44]
Symptoms of large cell lymphomas
Constitutional symptoms are uncommon in non-Hodgkin lymphoma, except in patients with
anaplastic large cell lymphoma (LCL). Many of these patients have low-grade fever, malaise,
anorexia, and/or weight loss. Because LCLs are biologically disparate, however, these lesions
have a varied presentation that may include chest or abdominal complications. In rare cases,
an LCL appears as an isolated bone lesion in association with pain, swelling, and a risk of
pathologic fracture.

Patients with anaplastic LCLs sometimes present with painful skin lesions, bone lesions,
[45, 46]
peripheral lymphadenopathy, and hepatosplenomegaly. The painful skin lesions may
regress spontaneously. A finding less common than these is testicular, lung, or muscle
involvement.
Anaplastic LCLs may also result in an apparent cytokine storm, with fevers, vascular leakage,
and pancytopenia.
Symptoms of CNS involvement
Patients occasionally develop symptomatic CNS involvement before diagnosis. Headache,
meningismus, cranial nerve palsies, and altered sensorium may be observed. Although CNS
involvement is uncommon at the time of diagnosis, patients with non-Hodgkin lymphoma
(particularly SNCCL) occasionally present with symptoms suggestive of meningoencephalitis.

Other
Among the less common lymphomas of childhood, primary cutaneous/subcutaneous
involvement can be seen (eg, in cutaneous T-cell lymphoma or blastic plasmacytoid dendritic
cell hematodermic neoplasm).

Physical Examination
Patients with non-Hodgkin lymphoma generally appear mildly to moderately ill. They
occasionally have a low-grade fever. Patients may present with pallor, respiratory distress,
pain, and discomfort.
A jaw or orbital mass is present in as many as 10% of patients in industrialized countries, but
this finding is particularly common in African patients with endemic Burkitt lymphoma.
Other clinical findings in non-Hodgkin lymphoma include the following:
Cervical or supraclavicular masses or adenopathy is/are firm, fixed, and nontender
Dyspnea or stridor may occur in patients with a mediastinal mass
In patients with superior vena cava syndrome, distended neck veins and plethora may be
observed
Decreased breath sounds are secondary to bronchial obstruction or pleural effusion
Thoracic dullness to percussion may be present with pleural effusion.
Abdominal distention or a mass may be present with or without tenderness, rebound
tenderness, and/or shifting dullness
Painful skin lesions suggest an anaplastic large cell lymphoma (LCL); the less common
forms of cutaneous lymphoma (T-cell, blastic plasmacytoid dendritic) are typically
nontender
Obtundation, agitation, and meningismus may be observed in individuals with CNS
involvement.
Focal pain or swelling in the extremity may be present in patients with primary bone
lymphoma.
Relatively uncommon physical findings include the following:
Nasopharyngeal mass
Parotid enlargement
Nephromegaly
Testicular enlargement
Diagnostic Considerations
Conditions to consider in the differential diagnosis of non-Hodgkin lymphoma include the
following:
Neuroblastoma
Rhabdomyosarcoma
Sarcoidosis
Toxoplasmosis
Tuberculosis
Wilms tumor
Differential Diagnoses
Acute Complications of Sarcoidosis
Atypical Mycobacterial Infection
Cat Scratch Disease (Cat Scratch Fever)
Hodgkin Lymphoma
Intussusception
Lymphadenitis
Lymphoproliferative Disorders
Pediatric Acute Lymphoblastic Leukemia
Pediatric Acute Myelocytic Leukemia
Pediatric Appendicitis
Pediatric Mononucleosis and Epstein-Barr Virus Infection
Pediatric Neuroblastoma
Pediatric Rhabdomyosarcoma
Toxoplasmosis
Tuberculosis
Wilms Tumor
Approach Considerations
A complete blood count (CBC) with differential and a platelet count in patients with non-
Hodgkin lymphoma should be obtained to assess for possible involvement of the bone marrow
and to determine the patient's transfusion requirements. Additional tests, listed in the next
section, are run to assess the patient's renal and hepatic function and to monitor for possible
tumor lysis syndrome.

Lumbar puncture

Lumbar puncture with determination of the cerebrospinal fluid (CSF) cell count and
differential is performed to assess CNS involvement, the presence of which alters therapy.

Airway obstruction

Mediastinal or cervical lymphomas may cause airway compromise. The potential for
respiratory arrest must be recognized, particularly if sedation or general anesthesia is
administered for a diagnostic procedure.
Consider (1) administering local anesthesia alone for lymph node biopsy; (2) establishing a
diagnosis with pleural fluid, peritoneal fluid, or bone marrow aspiration; and (3) performing
local irradiation to stabilize the airway before obtaining a diagnostic specimen from a site
outside the radiation field.
Laboratory Studies
As previously mentioned, a CBC with differential and a platelet count should be obtained in
patients with non-Hodgkin lymphoma to assess for possible involvement of the bone marrow
and to determine the patient's transfusion requirements.
Measure the prothrombin time, the activated partial thromboplastin time, fibrinogen, and the
D-dimer level if the patient is febrile or if he or she has evidence of sepsis. The purpose is to
assess for possible disseminated intravascular coagulation, which may require specific therapy.
Obtain blood and urine cultures if the patient has a fever, especially if it is associated with
neutropenia. If indicated, also obtain stool and throat cultures.
Analyze the following to assess the patient's renal and hepatic function and to monitor for
possible tumor lysis syndrome:
Serum electrolytes
Blood urea nitrogen (BUN)
Creatinine
Uric acid
Lactate dehydrogenase The level of lactate dehydrogenase at diagnosis has had
prognostic significance in many analyses of treatment outcomes
Bilirubin
Albumin
Total protein
Aspartate aminotransferase
Alanine aminotransferase
Calcium
Magnesium
Phosphorus
Imaging Studies

Chest radiography

Obtain posteroanterior and lateral views to assess for possible mediastinal masses, to evaluate
the airway, and to exclude pulmonary parenchymal lesions and associated pneumonia.

Ultrasonography

Abdominal ultrasonography helps in assessing the size of the kidneys and the patency of the
urinary tract. It is particularly useful before chemotherapy in anticipation of, for example,
prolonged excretion and excess toxicity. When symptoms are present, testicular
ultrasonography aids in identifying additional sites of disease.

Echocardiography

Perform echocardiography to obtain baseline findings before patients are given chemotherapy
with anthracyclines, which can cause cardiomyopathy.

CT scanning

Computed tomography (CT) scans of the chest, abdomen, and pelvis can be used to stage
lesions. If the patient is stable, chest CT scan is indicated to assess for the degree of tracheal
compression. Head CT scans assist in excluding mass lesions and possible meningeal
involvement in individuals with CNS disease.

PET/CT scanning

Positron emission tomography (PET)/CT scanning has largely supplanted gallium-67 (67 Ga)
scanning and is highly recommended for patients with non-Hodgkin lymphoma. [47, 48, 49, 50, 51]
Many lymphomas are 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) avid; their response to
treatment can be assessed by using this modality. Occult sites of disease may also be identified
on PET/CT scans. Many newer "response-based" chemotherapy protocols use PET scanning
to assess response and guide subsequent treatments.

Bone scanning and skeletal surveys

When additional symptoms are present, these tests help in identifying additional sites of
disease.
Serologic Analyses
Other tests may include serologic analyses for varicella, measles, herpes simplex
virus, Epstein-Barr virus, cytomegalovirus (CMV), hepatitis A, hepatitis B, and hepatitis C.
Perform these tests to document susceptibility in patients who will be receiving
immunosuppressive therapy. In addition, these tests may provide evidence of the cause (eg,
Epstein-Barr virus).
Serologic results can help in identifying patients who may benefit from transfusion with CMV-
negative blood products, especially if bone marrow transplantation is eventually offered. As
noted above, however, this is a marginal/arguable recommendation.
Order these tests to confirm previous exposure to a hepatitis virus before blood transfusions
are administered.

HIV infection

Non-Hodgkin lymphoma, particularly a primary tumor of the CNS, can be a presenting sign of
immunodeficiency, such as that resulting from HIV/acquired immunodeficiency syndrome
(AIDS). Perform HIV serologic tests in patients who have risk factors for HIV exposure or in
individuals with primary CNS lymphoma.

Biopsy and Paracentesis


A histologic diagnosis must be obtained. Flow cytometric analysis of tumor cell markers has
become the standard for lymphoma subtyping. [52] Cytogenetic analysis is sometimes helpful in
equivocal cases.
For patients with an abdominal tumor, tissue is generally available from resection or
intraoperative biopsy.
Patients with mediastinal disease frequently have enlarged supraclavicular or cervical nodes,
which can enable diagnosis without thoracotomy.
As an alternative, a diagnosis may be made by using pleural/peritoneal fluid or involved bone
marrow (especially if the CBC is abnormal and/or if imaging studies demonstrate abnormal
signal intensity of the marrow). In rare cases, cerebrospinal fluid (CSF) can be used.

Bone marrow aspiration and biopsy

Biopsy is necessary to assess for evidence of bone marrow involvement in patients with
lymphomas, with bilateral biopsy being superior to a unilateral procedure. Bone marrow
aspiration is potentially less sensitive than a core biopsy.
A finding of more than 25% marrow blasts is generally regarded as diagnostic of acute
leukemia. levels of lymphoma involvement lower than this indicate stage 4 disease.
Polymerase chain reaction (PCR) assays are being used experimentally to detect and monitor
minimal residual disease in the marrow. [53, 54] In the future, postinduction measurement of
minimal residual disease may improve precision in determining treatment responses and/or
treatment assignments.

Histologic Findings
Several classification systems for non-Hodgkin lymphoma are available. Examples are the Kiel
classification system and the NCI Working Formulation. At present, the Revised European-
American Lymphoma (REAL) classification system is gaining acceptance as the criterion
standard for classifying adult non-Hodgkin lymphoma. For classifying childhood non-Hodgkin
lymphoma, this system is overly complicated because it includes numerous diagnoses that are
rarely or never observed in children.

Adult non-Hodgkin lymphomas are characterized as low, intermediate, or high grade, and they
can have a diffuse or nodular appearance. In contrast, childhood non-Hodgkin lymphomas are
almost always high grade and diffuse. In general, they can be divided into 3 major classes, or
even 4 classes if one differentiates the 2 most common types of large cell lymphomas (LCLs),
B-cell and T-cell LCLs. The 3 major classeslymphoblastic lymphomas, small noncleaved
cell lymphomas (SNCCLs), and LCLsare described below.

For a particular tumor, achieving agreement among pathologists is sometimes difficult.


However, synthesis of the histologic, immunohistochemical, cytogenetic, and clinical and/or
anatomic data almost always results in a clear diagnosis.
Lymphoblastic lymphomas
Lymphoblastic lymphoma cells are indistinguishable from the lymphoblasts of acute
lymphoblastic leukemia (ALL). The cells are monotonous and associated with a high nuclear-
to-cytoplasmic ratio. Their nuclei are often convoluted and contain finely stippled chromatin.
Nucleoli are usually visible but are not prominent.

Immunohistochemical analysis usually reveals T-cell markers, including CD5 and CD7.
Common ALL antigen (CALLA) is occasionally observed.

A minor subset of lymphoblastic lymphomas expresses the precursor B-cell phenotype typical
of childhood ALL. This phenotype includes the surface antigens CALLA and B4 and the
human leukocyte antigen (HLA)DR.

Small noncleaved cell lymphomas


Small noncleaved cell lymphomas (SNCCLs) can be classified as Burkitt or non-Burkitt
(Burkittlike) lymphomas. The distinction may be subtle, and its clinical significance is unclear.

Burkitt lymphoma cells are notably uniform in size and shape, and they usually contain
multiple prominent nucleoli. In contrast, extensive cellular pleomorphism, or occasionally the
presence of a single nucleolus in most cells, suggests a diagnosis of Burkittlike lymphoma.
SNCCL cells have slightly more cytoplasm than do lymphoblastic lymphoma cells. The
cytoplasm is basophilic and usually contains lipid-filled vacuoles.

Macrophages often infiltrate the tumors, lending the classic starry-sky appearance. However,
this observation is not pathognomic of Burkitt lymphoma.

The tumor cells are mature B cells, as evidenced by the surface expression of immunoglobulin
(usually immunoglobulin M), CD19, CD20, and HLA-DR. CALLA is usually present.

Immunophenotyping results suggest that Burkittlike lymphoma cells are more likely than
Burkitt lymphoma cells to express the BCL-6 oncogene, and they exhibit relatively low levels
of apoptosis. [55]

Because of the features described, Burkittlike lymphoma appears to be biologically distinct


from Burkitt lymphoma; it is perhaps most closely related to the B-cell LCLs.

Large cell lymphomas


LCLs are a heterogeneous group, with LCL in most cases being classified as the B- or T-cell
type. The B-cellderived LCLs histologically merge with the SNCCLs. In terms of the
expression of cell-surface proteins, these tumors are currently indistinguishable. If infiltrating
macrophages are present, these cells can serve as a reference by which the tumor cells are
measured. In B-cell LCLs, many or most of the tumoral nuclei are larger than those of the
macrophages. B-cell LCLs can be divided into germinal center and nongerminal center
subtypes, a distinction that carries prognostic significance in adult patients; in pediatric
patients, germinal-center type B-LCLs predominate, which explains, in part, the overall better
outcomes for pediatric patients (versus adults) with B-cell LCL. [56]

Anaplastic LCLs are more common than B-cell LCLs and are derived from T cells, as
evidenced by their TCR gene rearrangements. However, anaplastic LCLs may express few T-
cell surface markers. Their hallmark is the expression of CD30, or Ki-1, an antigen first
recognized on Hodgkin lymphoma cells. Aberrant expression of myeloid markers CD13 and
CD33 has more recently been reported as a sensitive (but not specific) marker of ALK+
anaplastic LCL. [57]

Other cell surface markers that may be observed are HLA-DR and the IL-2 receptor. Finally,
a small number of LCLs do not exhibit a clear T-cell or B-cell phenotype. At least some of
these tumors are of histiocytic origin.
Staging
Several systems for classifying non-Hodgkin lymphomas have been proposed. The St Jude
system (ie, the Murphy system) has gained the widest acceptance. [58] This system is as follows:
Stage I - Single extranodal tumor or single anatomic area (nodal), excluding the
mediastinum or abdomen
Stage II - Single extranodal tumor with regional node involvement; primary
gastrointestinal (GI) tumor with or without associated involvement of mesenteric nodes,
with gross total resection; or, on the same side of the diaphragm, 2 or more nodal areas,
or 2 single (extranodal) tumors with or without regional node involvement
Stage III - Any primary mediastinal, pleural, or thymic intrathoracic tumor; any extensive
and unresectable abdominal tumor; any primary paraspinous or epidural tumor regardless
of other sites; or, on both sides of the diaphragm, 2 or more nodal areas, or 2 single
(extranodal) tumors with or without regional node involvement
Stage IV - Any of the above with initial CNS or marrow (< 25%) involvement

Approach Considerations
Proper care of non-Hodgkin lymphoma requires a referral to a comprehensive tertiary care
center. The current intense treatment regimens, particularly those for advanced stages of the
disease, necessitate inpatient administration of chemotherapy, as well as aggressive support by
a team experienced in the care of children with immunosuppression.

Current treatment regimens for lymphoblastic lymphomas (T cell and B cell) are quite similar
to protocols for their leukemic counterparts (T-cell ALL and B-cell ALL). In broad terms, these
therapies are longer and less intensive (particularly with respect to the use of alkylating agents)
than those for small noncleaved-cell lymphoma or LCL, which use relatively high doses of
alkylating agents and antimetabolites.

Current survival rates for patients with advanced disease are 65-75% for T-cell lymphoblastic
lymphomas and 80-90% for those with B-cell lymphomas.

Antibiotics
If present, fever simply may reflect the underlying malignancy. However, consider beginning
empiric, broad-spectrum antibiotic coverage until sepsis or focal infection (eg, due to bowel
perforation) is excluded.
Central venous access
For most patients, a central venous access device is necessary to manage chemotherapy. If
feasible, multiple procedures (eg, line placement, biopsy, lumbar puncture, bone marrow
aspiration) can be performed during one session of anesthesia.
As noted previously, patients with mediastinal disease must be treated cautiously if the use of
general anesthesia is being considered. Unrecognized airway compression can lead to
obstruction, with disastrous consequences.
Rapid progression
Non-Hodgkin lymphomas in children typically grow rapidly, in contrast to the more indolent
lymphomas often observed in adults.
To prevent tumoral regrowth and to avoid increasing the short-term risk of complications,
absolutely minimize any delay (eg, to allow healing after an abdominal procedure) between
diagnosis and the start of chemotherapy.

Tumor Lysis Syndrome Treatment


Before and during the initial induction phase of chemotherapy, patients may develop tumor
lysis syndrome, a condition that can result from the rapid destruction of a large number of
neoplastic cells. This destruction causes intracellular ions and metabolic byproducts to be
released into the systemic circulation, which can lead to the rapid development of
hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. (Renal involvement by
lymphoma is an additional risk factor.)
Hyperuricemia or tubular obstruction may lead to acute renal failure, requiring dialysis. In
general, this is not a contraindication to continuing chemotherapy. However, some protocols
now include a preliminary phase of relatively gentle cytoreductive chemotherapy designed to
avoid these metabolic complications.
With all patients, administer intravenous fluids at twice the maintenance rates, usually without
potassium. Add sodium bicarbonate to the intravenous fluid to achieve moderate alkalinization
of the urine (pH of approximately 7). This measure enhances the excretion of tumor
metabolites. For example, the solubility of uric acid is 10-12 times higher at a pH of about 7
than it is at a pH of 5, and the solubility of xanthine is doubled. Avoid a urine pH higher than
this to prevent crystallization of hypoxanthine or calcium phosphate.
Administer allopurinol to prevent or correct hyperuricemia. In high-risk situations (extreme
elevations of lactate dehydrogenase [LDH] and/or uric acid or evidence of impaired renal
function at presentation), consider administration of recombinant urate oxidase (rasburicase
[Elitek]).[59]
Follow up the patient's laboratory values to monitor tumor lysis syndrome throughout initial
therapy. Testing may be needed as often as 2-4 times per day. This follow-up is especially
important during the first 48-72 hours of therapy in a patient with bulky disease.
Chemotherapy for Lymphoblastic Lymphoma
The most successful treatment protocols for advanced-stage lymphoblastic lymphoma feature
chemotherapy combinations designed to treat acute lymphoblastic leukemia (ALL).

LSA2L2 protocol
The LSA2 L2 protocol evolved from ALL protocols used at the Memorial Sloan-Kettering
Cancer Center in the early 1960s. The LSA2 L2 protocol features 3 phases of therapynamely,
induction, consolidation, and repeated cycles of maintenancegiven over a total of 2-3 years.
[60]
Methotrexate is administered intrathecally for CNS prophylaxis throughout treatment.
When this protocol was first described, it included irradiation of sites of bulky disease;
however, radiation is no longer routinely applied.

Children's Cancer Group protocol 552


Between 1986 and 1989, 143 subjects with lymphoblastic lymphoma (10% with localized
disease) received treatment with a modified LSA2 L2 regimen in a Children's Cancer Group
trial (see Table 1, below). Their 5-year event-free survival rate was 74%. [61]

Table 1. Modified LSA2 L2 Therapy in Children's Cancer Group Protocol 552 (Open Table in
a new window)
Phase Drug Route
Cyclophosphamide,
Induction vincristine, IV
daunorubicin
Ara-C, methotrexate IT

Prednisone PO

Consolidation Ara-C IV or SC

6-thioguanine PO

Methotrexate IT

L-asparaginase IM

BCNU IV

Phase Cycle Drug Route


6-
Maintenance* 1 PO
thioguanine
Cyclophosphamide IV

2 Hydroxyurea PO

Daunorubicin IV

3 Methotrexate PO

BCNU IV

4 Ara-C IV or SC

Vincristine IV
Source: Children's Cancer Group

Ara-C = cytarabine; BCNU = 1,3-bis(2-chloroethyl)-1-nitrosourea, or carmustine; IM =


intramuscular; IT = intrathecal; IV = intravenous; PO = oral; SC = subcutaneous

*
A minimum of 5 repeated courses (total duration of therapy >18 mo) are noted. Each course
of intrathecal methotrexate (day 0 of each course) consists of 4 cycles of rotating drug pairs
that are administered every 2 weeks after blood counts have recovered.

German Berlin, Frankfurt, Muenster treatment protocol


The German Berlin, Frankfurt, Muenster (BFM) protocols have demonstrated excellent results
in patients with ALL or lymphoblastic lymphoma. (See Table 2, below.) [62]

Unlike the LSA2 L2 protocol, the BFM regimen has a reinduction phase. It also features a less
complicated and less intense maintenance phase. In its original report, the BFM protocol
included prophylactic cranial irradiation during reinduction. Patients receiving this treatment
had a 6-year event-free survival rate of 79%.

Table 2. Therapy for Stage III and IV NonB-Cell Disease* According to BFM Protocol 86
(Open Table in a new window)
Phases Drug Route
Prednisone, 6-
Induction PO
mercaptopurine
Vincristine, daunorubicin, cyclophosphamide, Ara-C IV

L-asparaginase IM

Methotrexate IT
6-
Consolidation PO
mercaptopurine
Methotrexate with leucovorin rescue IV

Methotrexate IT
Dexamethasone,
Re-induction PO
6-thioguanine
Vincristine, doxorubicin, cyclophosphamide, Ara-C IV

L-asparaginase IM

Methotrexate IT
6-
Maintenance mercaptopurine, PO
methotrexate
Source: Berlin-Frankfurt-Munster Group

Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral; SC = subcutaneous

*
Diagnoses included lymphoblastic lymphoma of the T-cell or precursor B-cell type,
immunoblastic T-cell lymphoma, and other peripheral T-cell lymphomas. Of note, patients
with Ki-1+ anaplastic large cell lymphomas (LCLs) were not included.


Continued until 24 months after diagnosis.

Children's Oncology Group protocols


The most recent Children's Oncology Group phase 3 protocol (A5971) for children with
advanced-stage T-cell lymphoblastic lymphoma featured a 4-way randomization between (1)
BFM therapy, (2) a Children's Cancer Group modified version of BFM therapy (which did not
include high-dose methotrexate/leucovorin during consolidation), and (3) intensified versions
of these 2 protocols (with early introduction of daunomycin and cyclophosphamide). In
patients with disseminated disease, there was no statistical difference in outcomes among the
4 groups, with 5-year event-free survival of approximately 81%. Age younger than 10 years
and imaging response at 2 weeks were associated with better overall survival. [63]

The Children's Oncology Group is conducting specific protocols to treat T-lymphoblastic


lymphoma and T-cell ALL. In particular, current clinical trials will examine the role of
nelarabine (previously known as compound 506U78), a prodrug of the deoxyguanosine analog
9-beta-D-arabinofuranosylguanine (Ara-G) that has shown efficacy in T-cell malignancies.

Additional treatment details


For advanced-stage lymphoblastic lymphoma, as for ALL, relatively long intervals of
treatment have been most successful. The maintenance phase typically lasts 18-30 months.
Protocols shorter than this have also been investigated. For example, Children's Cancer Group
protocol 5941 examined an aggressive, 11-month, multiagent regimen. In this trial, the 5-year
event-free survival rate was 78% 4.5%, and the overall survival rate was 85% 3.9%. These
results suggest that the experimental approach is safe and is just as effective as more prolonged
regimens. [64]
When results from several series were combined, patients appeared to have an excellent
prognosis. Long-term survival was approximately 80%.

Despite these findings, a consensus about optimal therapy for lymphoblastic lymphoma is
lacking. Treatment options include the LSA2 L2 protocol and BFM protocol 86 for non-
Hodgkin lymphoma (with the reinduction phase eliminated).

Localized lymphoblastic lymphoma is unusual. In the previously mentioned BFM study, 6 of


77 subjects with nonB-cell non-Hodgkin lymphoma had stage I or II disease. Patients with
localized lymphoblastic lymphoma (n=60) were included in Children's Oncology Group
protocol A5971; they received a Children's Cancer Group modified version of the BFM
protocol (as described above) that included reinduction but had fewer doses of intrathecal
chemotherapy during the maintenance phase. Interestingly, most patients (75%) had a B-
precursor phenotype. At a median follow-up of 5.9 years, the 5-year event-free survival rate
was 90% (95% confidence interval, 78-96%, with an overall survival rate of 96% [84-99%]).
There were no relapses among the 15 T-cell lymphoblastic lymphoma subjects. [65]

Regimens simpler than these have demonstrated comparable results. For example, protocol 77-
04 from the NCI included alternating cycles of cyclophosphamide, doxorubicin, vincristine,
and prednisone (CHOP) and high-dose methotrexate (with leucovorin as rescue therapy).
Aggressive intrathecal prophylaxis with cytarabine and methotrexate was included; local
radiation therapy was not offered routinely. The total duration of therapy was 15 cycles
(approximately 60 wk).

Chemotherapy for Small Noncleaved Cell Lymphoma


Since the mid-1980s, survival rates for patients with Burkitt or Burkittlike lymphomas have
increased dramatically. In general terms, the following lessons have been learned:
Long-term maintenance chemotherapy appears to have no role; therefore, chemotherapy can
be short, with the typical duration being 2-6 cycles, each lasting 3-4 weeks (however,
the intensity of treatment is high for most patients, and inpatient treatment is required)
When observed, relapses occur early, either during therapy or within 6-12 months of its
completion; salvage rates for patients with relapse have been disappointing
Even patients with widely disseminated disease (eg, bone marrow involvement) have a long-
term survival rate of 90%
Involvement of the CNS at diagnosis continues to be an adverse prognostic indicator

Treatment protocol from a Cooperative Group trial


Three cooperative groups conducted an international trial for patients with small noncleaved
cell lymphoma (SNCCL); specifically, the French Society of Pediatric Oncology (SFOP), in
France, Belgium, and the Netherlands; the Children's Cancer Group, in the United States,
Canada, and Australia; and the United Kingdom Children's Cancer Study Group (UKCCSG),
in the United Kingdom and Ireland.

Chemotherapy was based on the SFOP LMB-89 study, in which event-free survival rates
ranged from 100% in group A to 87.5% in group C. Patients with B-cell acute lymphoblastic
leukemia (ALL) were included in this protocol. Subjects were staged (as described above) and
then were assigned to clinical risk groups. (See Tables 3, 4, 5, and 6, below.)

Table 3. Clinical Risk Groups in the International Trial for Patients With SNCCL (Children's
Cancer Group study 5961) (Open Table in a new window)
Subjects,

Clinical
Estimated Definition
Group
%
A 10 All resected stage I or abdominal stage II tumors

Unresected stage I or II tumor, stage III, tumor, or stage IV


B 65
tumor with no CNS involvement and < 25% marrow blasts

C 25 CNS involvement or >25% marrow blasts

Table 4. Standard Therapy in the International Trial for Patients With SNCCL, Group A* (Open
Table in a new window)
Drug Route
Prednisone PO
Vincristine, cyclophosphamide, doxorubicin IV
Filgrastim (G-CSF), to enhance neutrophil recovery SC or IV
G-CSF = granulocyte colony-stimulating factor; IV = intravenous; PO =
oral; SC = subcutaneous

*
See Table 3 for the definition of group A. All subjects received 2 cycles.

With median follow-up of more than 4 years, the 4-year event-free survival rate for group A
patients was 98.3%, and the overall survival rate was 99.2%. [66]

In this trial, patients with advanced disease (groups B and C) received an initial moderately
intensive "reduction" phase of chemotherapy. This was intended to reduce the tumor burden
with minimal risk of inducing or exacerbating tumor lysis syndrome. Patients in group B were
randomized to 1 of 4 treatment arms: the 3 experimental treatment arms involved incremental
decreases in the intensity and/or duration of chemotherapy.

For patients in group B with an "early response" to therapy (at least 20% tumor decrease after
7 days of treatment), outcomes with standard therapy were not superior to outcomes with any
of the experimental (reduced therapy) arms. (See Table 5, below.)

The results indicated, therefore, that pediatric patients with intermediate-risk B non-Hodgkin
lymphoma who have an early response and achieve a complete remission after the first
consolidation course can be effectively treated using a 4-course regimen with a total dose of
only 3.3 g/m2 cyclophosphamide and 120 mg/m2 doxorubicin. [67]

Table 5. Standard Therapy in the International Trial for Patients With SNCCL, Group B* (Open
Table in a new window)
Phase Drug Route
Reduction Prednisone PO
Vincristine,
IV
cyclophosphamide
Methotrexate/hydrocortisone IT

Phase Cycles Drug Route


2, starting 7 days after
Induction Prednisone PO
reduction
Vincristine, methotrexate with
leucovorin rescue, IV
cyclophosphamide, doxorubicin
Methotrexate/hydrocortisone IT

Filgrastim (G-CSF) SC or IV
Methotrexate
with
Consolidation 2 leucovorin
rescue, Ara-
C
Methotrexate/hydrocortisone, Ara-
C/hydrocortisone
Filgrastim (G-CSF)

Maintenance** 1 Prednisone PO
Vincristine, methotrexate with
leucovorin rescue, IV
cyclophosphamide, doxorubicin
Methotrexate/hydrocortisone IT
Ara-C = cytarabine; G-CSF = granulocyte colony-stimulating factor; IT = intrathecal; IV =
intravenous; PO = oral, SC = subcutaneous

*
See Table 3 for the definition of group B.
** Based on published results from this trial, equivalent outcomes are expected with a reduced
(50%) dose of cyclophosphamide in induction phase 2 and/or elimination of maintenance phase
1.

Group C patients in remission after 3 cycles were randomized to standard versus reduced-
intensity therapy (omitting the last 3 cycles of maintenance). The 4-year event-free survival
rate after randomization was 90% 3.1% versus 80% 4.2%, respectively, whereas the overall
survival rate was 93% 2.7% versus 83% 4%, respectively. Patients with either combined
marrow and CNS disease at diagnosis or a poor response to reduction therapy had significantly
inferior event-free survival and overall survival. [68]

Therefore, decreasing therapy in this subgroup of patients appears unwise; standard-intensity


therapy is recommended for children with high-risk B non-Hodgkin lymphoma. (See Table 6,
below.)

Table 6. Standard Therapy in the International Trial for Patients With SNCCL, Group C* (Open
Table in a new window)
Phase Drug Route
Reduction Prednisone PO
Vincristine, cyclophosphamide IV
Methotrexate/Ara-C/hydrocortisone IT

Induction, cycle 1 starting 7 days after reduction Prednisone PO


Vincristine, high-dose methotrexate with leucovorin
IV
rescue, cyclophosphamide, doxorubicin
Methotrexate/Ara-C/hydrocortisone IT

Filgrastim (G-CSF) SC or IV
Induction, cycle 2 Prednisone PO
Vincristine, high-dose methotrexate with leucovorin
IV
rescue, cyclophosphamide, doxorubicin
Methotrexate/Ara-C/hydrocortisone IT
Filgrastim (G-CSF) SC or IV
High-dose Ara-C,
Consolidation, 2 cycles IV
etoposide (VP-16)
Filgrastim (G-CSF), days 7-21 SC or IV

High-dose methotrexate with leucovorin rescue IV


Methotrexate/Ara-C/hydrocortisone IT

Maintenance 1 Prednisone PO
Vincristine, high-dose methotrexate with leucovorin
IV
rescue, cyclophosphamide, doxorubicin
Methotrexate/Ara-C/hydrocortisone IT
Ara-C, etoposide
Maintenance 2 IT
(VP-16)
Maintenance 3 Prednisone PO
Vincristine, cyclophosphamide, doxorubicin IV
Ara-C, etoposide
Maintenance 4 IV
(VP-16)
Ara-C = cytarabine; G-CSF = granulocyte colony-stimulating factor; IT = intrathecal; IV =
intravenous; PO = oral, SC = subcutaneous

*
See Table 3 for the definition of group C.


For patients with CNS involvement, during consolidation cycle 1 only.

An alternative treatment approach has been developed over a series of randomized trials by the
German Berlin, Frankfurt, Muenster (BFM) group. [69] In particular, the role of intermediate-
dose or high-dose methotrexate has been investigated among the different clinical risk groups.

Pilot protocols for patients with B-cell non-Hodgkin lymphoma include monoclonal antibodies
(eg, anti-CD20 rituximab) for children with high-risk disease (ie, patients with CNS disease at
diagnosis or those with advanced-stage disease and elevated levels of lactate dehydrogenase).

Chemotherapy for Large Cell Lymphoma


B cell derived LCLs
Patients with B cell derived large cell lymphomas (LCLs) are treated effectively using
regimens for SNCCL. [70, 71, 72] Outcomes are similar between the groups.

An alternative therapy is the APO regimen, consisting of doxorubicin (Adriamycin),


prednisone, and vincristine [Oncovin]. [73] Methotrexate and 6-mercaptopurine have been added
to this regimen.

A randomized study of children with LCLs (including B-cell LCLs) showed no advantage
when cyclophosphamide was added to the APO regimen. [74] Therefore, this therapy has the
advantage of avoiding exposure to an alkylating agent. However, the cumulative dose of
doxorubicin is 450 mg/m2.

Anaplastic (T cell derived) LCLs


The therapy for anaplastic (T-cell) LCLs is somewhat controversial. Good results (event-free
survival rates of 65-80%) have been reported with a number of protocols. Some were based on
acute lymphoblastic leukemia (ALL) therapy, whereas others were similar or identical to those
used to treat B-cell lymphomas.

The Berlin, Frankfurt, Muenster (BFM) group reported what may be the best results with
[75]
treatment for Ki-1+ anaplastic LCLs. The group administered a regimen for B-cell
lymphomas that did not include local radiation therapy. Among 62 patients (none with bone
marrow disease and 1 with CNS involvement), 4 did not achieve remission, 1 died from
infection, and 7 had a relapse. At the time of the report, 50 patients remained in a continuous
first episode of complete remission, and 56 were alive. The calculated event-free survival rate
at 9 years was 83%.
Subsequent modifications have yielded the ALCL99 protocol as shown below and have further
demonstrated that: (1) dosing methotrexate at 3 g/m2 over 4 hours appears to be at least as
effective (and less toxic) when compared with a dose of 1 g/m2 over 24 hours with the addition
of "triple" intrathecal chemotherapy and (2) the addition of vinblastine (both during
chemotherapy and continuing weekly until 1 year from diagnosis) delayed but did not
ultimately prevent relapses. [76, 77]

Table 7. Prephase Therapy for Ki-1+ Anaplastic LCLs According to the ALCL99 Protocol
(Open Table in a new window)
Drug Route
Dexamethasone PO
Cyclophosphamide IV

Methotrexate/Ara-C/prednisolone IT

Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral.

Table 8. Subsequent Therapy for Ki-1+ Anaplastic LCLs According to the ALCL99 Protocol
(alternating cycles, repeated 3times each) (Open Table in a new window)
Cycle Drug Route
A Dexamethasone PO
Methotrexate with leucovorin
rescue, ifosfamide, etoposide (VP- IV
16), Ara-C
B Dexamethasone PO
Methotrexate with leucovorin
rescue, cyclophosphamide, IV
doxorubicin
Ara-C = cytarabine; IT = intrathecal; IV = intravenous; PO = oral.

Good results have been observed with the relatively uncomplicated APO regimen. In addition,
a randomized study of children with LCL (including B-cell LCL and anaplastic LCL) showed
no apparent advantage when intermediate-dose methotrexate and high-dose cytarabine were
added to an APO backbone. [78]

A report from the SFOP described surprising efficacy for monotherapy with vinblastine for
relapsing anaplastic LCL, even in patients who previously underwent myeloablative therapy
with autologous bone marrow transplantation. [79]

The role of vinblastine in front-line therapy for anaplastic LCL was examined in a Children's
Oncology Group protocol (A5941), which compared the standard APO regimen with an
experimental therapy that included vinblastine. Myelosuppression was more significant than
anticipated and the trial closed early; results have not been published.

The current Children's Oncology Group Phase 2 protocol for anaplastic LCLs uses the ALCL99
regimen (shown above) as a "backbone" and adds (in a randomized fashion) either brentuximab
vedotin, an anti-CD30 monoclonal antibody, or crizotinib, a specific small-molecule inhibitor
of the ALK pathway. [80]
Radiation Therapy
In general, radiation therapy has a limited role in the treatment of pediatric non-Hodgkin
lymphoma, and it is applied almost exclusively in situations deemed to be real or potential
emergencies.
Mediastinal irradiation may be helpful in patients with impending airway obstruction,
especially if the use of general anesthesia is being contemplated for biopsy or central line
placement.
For patients with lymphoblastic lymphoma, low-dose radiation therapy is often used to treat
neurologic involvement (eg, cranial nerve palsies, intracerebral extension of tumor,
paraplegia).
Irradiation has minimal efficacy in patients with SNCCL, presumably because of the rapid
growth of these cells. Although a dose of radiation may result in significant cell kill, rapid
regrowth of surviving cells between doses largely negates the benefit. Hyperfractionated
radiotherapy (ie, >1 dose daily) offers a theoretic advantage, as does low-dose continuous
irradiation. However, the unfeasibility of the latter all but precludes its use.[81]
Finally, consider radiotherapy in any patient with documented residual disease after
chemotherapy and in patients with bulky disease at the time of relapse.
Treatment of Relapsed Disease
As front-line therapies for pediatric non-Hodgkin lymphoma continue to evolve and improve,
treatment of relapses is becoming increasingly problematic.
Reinduction regimens use novel chemotherapy combinations, such as ifosfamide, carboplatin,
and etoposide (ICE). Depending on the presence of certain cell-surface markers, monoclonal
antibodies (eg, the anti-CD20 antibody rituximab) may be added to the regimen. [82, 83]
In most cases, myeloablative chemotherapy with either autologous stem-cell rescue or
allogeneic bone marrow transplantation may offer the best option for curative consolidative
therapy.
Lymph Node Excision and Dissection
Even for patients with bulky non-Hodgkin lymphoma, debulking surgery is not crucial to
effective therapy. For example, chemotherapy is effective in relieving partial airway or bowel
obstruction. In rare instances, resection may be required for this purpose.
The chief role for surgery is obtaining tissue for diagnosis. Excision of an easily accessible
lymph node (when present) is preferable to a thoracotomy or laparotomy, unless symptoms
dictate otherwise. Even moderately aggressive surgery generally is not necessary or helpful.
One exception, and a potential therapeutic dilemma, involves abdominal B-cell non-Hodgkin
lymphoma. The patient can be assigned to clinical group A (see Table 3) if the following
conditions are met:
An intestinal primary lesion can be resected along with all involved adjacent lymph nodes
The marginal lymph nodes are free of disease
The patient has no evidence of further dissemination (eg, to the CNS or marrow)
In this situation, the prescribed chemotherapy regimen is far less toxic than it would be
otherwise. Therefore, a surgeon treating a reasonably small abdominal non-Hodgkin
lymphoma is advised to perform lymph node dissection and to try to excise all visible areas of
tumor.
However, this surgery is performed only if it can be accomplished without causing clinically
significant morbidity. Heroic attempts at resection are best avoided because unresected disease
can still be cured in most patients. Furthermore, prolonged postoperative recovery may delay
the start of chemotherapy and potentially compromise its effectiveness.
Second-look surgery may be helpful for assessing the viability of residual masses, although
second-look procedures require highly individualized approaches. As an alternative, uptake
of67 Ga or radiolabeled FDG suggests viability of residual masses in patients whose tumors are
gallium or FDG avid.
Consultations
Intensive care specialist

Patients with pediatric non-Hodgkin lymphoma frequently present in a tenuous condition


because of airway compromise, metabolic derangements, and/or infection. In the initial stages
of therapy, the patient's condition may be unstable or deteriorating. Therefore, the support of a
pediatric intensive care unit is highly desirable.
If available, a pediatric intensivist should be made aware of the patient in the event that
respiratory management or pressor support becomes necessary.

Radiation oncologist

Consider consultation with a radiation oncologist. As previously discussed, however, radiation


therapy generally has a limited role in the treatment of pediatric non-Hodgkin lymphoma, and
it is applied almost exclusively in situations deemed to be real or potential emergencies.

Nephrologist

Notify a nephrologist if the patient has substantial tumor lysis syndrome and if dialysis is under
consideration.
Long-Term Monitoring
A study of a cohort of 200 childhood non-Hodgkin lymphoma survivors found that common
late outcomes in adulthood included obesity (35%), hypertension (9%), and impairment of
executive function (13%), attention (9%), and memory (4%). The study also found a prevalence
of impaired strength (48%), flexibility (39%), muscular endurance (36%), and mobility (36%)
in the cohort.[84]
Medication Summary
The agents described below are used in combination regimens, and doses are tailored to the
histologic subtype of lymphoma and the stage of disease present.
In addition to the use of chemotherapeutic drugs, treatment also includes the employment of
several classes of medications to support patients with non-Hodgkin lymphoma undergoing
aggressive chemotherapy. These include the following:
Laxatives and stool softeners
Prophylactic antibiotics
Antiemetics
Antimucositic agents
Histamine (H2) receptor antagonists
Contraceptives
Prophylactic antibiotics

These medications include the following:


Trimethoprim-sulfamethoxazole (against Pneumocystis jiroveci [formerly, carinii])
Fluconazole (against Candida species)
Nystatin (against Candida species)
Antiemetics
Antiemetics include the following:
Serotonin (5-hydroxytryptamine type 3 [5-HT3]) receptor antagonists (ondansetron,
granisetron, dolasetron)
Phenothiazine
Lorazepam
Metoclopramide
Dexamethasone
Tetrahydrocannabinol

Antimucositic agents
These agents include the following:
Saline or bicarbonate rinse
Biotene rinse
Peridex rinse
Glutamine suspension
Histamine (H2) receptor antagonists

Famotidine and ranitidine help to prevent gastritis in patients receiving high-dose


corticosteroids.

Contraceptives

Oral or injectable contraceptives can be used to suppress menses in female adolescents at risk
for menorrhagia due to thrombocytopenia.
Corticosteroids
Class Summary

Corticosteroids elicit anti-inflammatory properties and cause profound and varied metabolic
effects. They modify the body's immune response to diverse stimuli.

Methylprednisolone (Medrol, A-Methapred, Solu-Medrol)

View full drug information


The mechanism of cytotoxicity for methylprednisolone is unknown, but it is apparently
mediated by glucocorticoid receptors.

Dexamethasone (Baycadron)

View full drug information


The mechanism of cytotoxicity for dexamethasone is unknown, but it is apparently mediated
by glucocorticoid receptors. The drug's action is apparently enhanced by CNS penetration
(relative to prednisone).
Antibiotics, Other

Class Summary

Therapy should cover all likely pathogens in the context of this clinical setting.

Trimethoprim and sulfamethoxazole (Bactrim, Bactrim DS, Septra DS)

View full drug information


Trimethoprim/sulfamethoxazole inhibits bacterial growth by inhibiting the synthesis of
dihydrofolic acid. The antibacterial activity of trimethoprim/sulfamethoxazole
includes Pneumocystis jiroveci.
Antifungals

Class Summary

These agents may change the permeability of the fungal cell resulting in a fungicidal effect.

Fluconazole (Diflucan)

View full drug information


Fluconazole is a synthetic oral antifungal agent (a broad-spectrum bistriazole) that selectively
inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation.
Nystatin

View full drug information


Nystatin is a fungicidal and fungistatic antibiotic obtained from Streptomyces noursei. It is
effective against candidal organisms. It changes the permeability of the fungal cell membrane
after binding to cell membrane sterols, causing cellular contents to leak.

Antiemetic Agents
Class Summary
Antiemetics are always prescribed before and after the administration of chemotherapy, for the
prevention of chemotherapy-induced nausea and vomiting.

Ondansetron (Zofran, Zuplenz)


View full drug information

Ondansetron is a selective 5-HT3 receptor antagonist that blocks serotonin peripherally and
centrally. It prevents nausea and vomiting associated with emetogenic cancer chemotherapy
(eg, high-dose cisplatin) and whole-body radiotherapy.

Granisetron (Kytril, Granisol, Sancuso)


View full drug information

At the chemoreceptor trigger zone, granisetron blocks serotonin centrally and peripherally on
vagal nerve terminals.

Palonosetron (Aloxi)
View full drug information

Palonosetron, is a selective 5-HT3 receptor antagonist with a long half-life (40 h). It is a
selective 5-HT3 receptor antagonist that blocks serotonin peripherally and centrally. It prevents
nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose
cisplatin) and whole-body radiotherapy.

Dolasetron (Anzemet)
View full drug information

At the chemoreceptor trigger zone, granisetron blocks serotonin centrally and peripherally on
vagal nerve terminals.

Metoclopramide (Reglan, Metozolv)


View full drug information

The antiemetic effect of metoclopramide appears to be due to its ability to block dopamine
receptors in the chemoreceptor trigger zone (CTZ) of the central nervous system (CNS). This
agent also enhances gastrointestinal motility and accelerates gastric emptying time.

Lorazepam (Ativan)
View full drug information

Lorazepam is a benzodiazepine used as an antiemetic in patients receiving chemotherapy for


non-Hodgkin disease. By increasing the action of gamma-aminobutyric acid (GABA) the
major inhibitory neurotransmitter in the brain, lorazepam may depress all levels of the CNS,
including the limbic system and the reticular formation.

Chlorpromazine
View full drug information

The antiemetic effect of metoclopramide appears to be due to its ability to block dopamine
receptors in the chemoreceptor trigger zone (CTZ) of the central nervous system (CNS).

Dronabinol
View full drug information

This agent inhibits endorphins in the brain's emetic center through an unknown mechanism.
Histamine H2 Antagonists
Class Summary

Like antacids, these agents decrease the amount of acid in the refluxate by inhibiting acid
production. These agents are used to help prevent gastritis in patients receiving high-dose
corticosteroids. All H2 -receptor antagonists are equipotent when used in equivalent doses. H2 -
receptor antagonists are considered the drugs of choice for children because pediatric doses are
well established and the medications are available in liquid form.

Nizatidine (Axid)

View full drug information


Nizatidine competitively inhibits histamine at the H2 receptor of the gastric parietal cells,
resulting in reductions in gastric acid secretion, gastric volume, and hydrogen concentrations.

Ranitidine (Zantac)

View full drug information


Ranitidine inhibits histamine stimulation of the H2 receptor in gastric parietal cells, reducing
gastric acid secretion, gastric volume, and hydrogen ion concentrations.

Famotidine (Pepcid)

View full drug information


Famotidine competitively inhibits histamine at the H2 receptors of gastric parietal cells,
reducing gastric acid secretion, gastric volume, and hydrogen ion concentrations.
Progestins

Class Summary

These agents may induce endometrial thinning by inhibiting the secretion of pituitary
gonadotropins.

Norethindrone acetate (Aygestin, Camila, Errin)

View full drug information


Norethindrone is a common progestin used in many of the oral contraceptive pills currently
available. Progestins stop endometrial cell proliferation, allowing organized sloughing of cells
after withdrawal. These agents typically do not stop acute bleeding episode, but they produce
normal bleeding episodes following withdrawal.
Medroxyprogesterone (Depo-Provera, Provera)

View full drug information


Progestins stop endometrial cell proliferation, allowing organized sloughing of cells after
withdrawal. These agents typically do not stop acute bleeding episode, but they produce normal
bleeding episodes following withdrawal.
Medroxyprogesterone is a common progestin available in both an oral and an intramuscular
depo form. The efficacy and adverse effects of this drug are similar to those of norethindrone.
Estrogens/Progestins

Class Summary

Oral contraceptives may be used to decrease the amount of bleeding. Topical preparations can
be used to help strengthen the mucosa and decrease its susceptibility to bleeding. Before use,
screening tests for pulmonary AVMs should be performed because of the risk of complications
involving thromboembolism.

Norethindrone acetate and ethinyl estradiol (Aranelle, Balziva, Nortrel, Loestrin 1.5/30)

View full drug information


Norethindrone acetate and ethinyl estradiol are used to decrease mucosal bleeding. The
combination probably works by strengthening mucosal tissues and thereby making them more
resistant to bleeding.
Uricosuric Agents

Class Summary

These agents control hyperuricemia and are used to attempt to prevent urate nephropathy and
subsequent oliguric renal failure.
Allopurinol inhibits xanthine oxidase, thereby reducing uric acid. The IV form (Aloprim) may
be used for patients unable to tolerate oral administration.
Caution is necessary because of the high uric acid concentration in the urine. In the presence
of allopurinol, the excretion of uric acid, xanthine, and hypoxanthine increases several hundred
fold, enough to exceed their solubility limit in the renal tubules even at a urinary pH level of
7. Also, at a urinary pH level higher than 7.5, crystallization of hypoxanthine may occur, which
necessitates withdrawal of bicarbonate from IV fluids.
Allopurinol (Zyloprim, Alloprim)

View full drug information


Allopurinol inhibits xanthine oxidase, the enzyme that synthesizes uric acid from hypoxanthine
and xanthine, thus decreasing production and excretion of uric acid and increasing the levels
of more soluble xanthine and hypoxanthine. The drug reduces the synthesis of uric acid without
disrupting the biosynthesis of vital purines. Patient response is measured by serum uric acid
levels assessed at 48 hours after the initiation of therapy. Dosage adjustments are made as
needed.

Rasburicase (Elitek)

View full drug information


Rasburicase is a recombinant form of the enzyme urate oxidase, which oxidizes uric acid to
allantoin. It is indicated for the treatment and prophylaxis of severe hyperuricemia associated
with the treatment of malignancy. Hyperuricemia causes a precipitant in the kidneys, which
leads to acute renal failure. Unlike uric acid, allantoin is soluble and easily excreted by the
kidneys. The elimination half-life for rasburicase is 18 hours.

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