Module 2.

Blood and endocrine system diseases in children .

Lesson 2.

Topic: Leukemia and lymphoma in children. Etiology. Pathogenesis. Classification. Diagnostics. Differential diagnosis with other diseases of the blood and diseases proceeding with hyperplastic syndrome. Treatment. Emergency care with hemorrhagic syndrome and compression. Outlook.

 

Leukemia in children:

 

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.

Acute Lymphoblastic Leukemia

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.

The darkly-stained lymph cells (lymphoblasts) seen in acute lymphocytic leukemia.

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 iormal 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.

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.

TABLE 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)

 

TABLE 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, Ewing‘s sarcoma, leukemia, neuroblastoma
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. Philadelphia, WB Saunders, 1994.

 

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, Ewing‘s sarcoma, and retinoblastoma) can occasionally produce pancytopenia. These tumor cells are usually found in clumps scattered throughout normal marrow tissue but may occasionally replace the marrow completely. Evidence of a primary tumor is usually found in some other site.

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 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 PO

   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 PO × 7 days every 4 wks

MTX = methotrexate; HC = hydrocortisone; Ara-C = cytarabine; IV = intravenous; PO = oral; IM = intramuscular; 6-MP = 6-mercaptopurine.

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 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 Philadelphia chromosome, and the t(4;11)–confer a poor prognosis. Some advocate bone marrow transplantation during initial remission in patients with these translocations. B-progenitor-cell ALL with the t(1;19) has a somewhat less promising prognosis than other cases with this immunophenotype; only 60% of patients will still be in remission after 5 yr unless intensive therapy is used. Rearrangement of TEL/AML1 genes in B-progenitor ALL appears to confer an exceptionally favorable prognosis, regardless of WBC count or age, and is present in 25% of this phenotype of ALL.

 

Acute Myeloid Leukemia

 

AML accounts for 15-20% of the approximately 2,500 cases of pediatric leukemia diagnosed in the United States annually. Certain genetic conditions, such as trisomy 21, Diamond-Blackfan syndrome, Fanconi’s aplastic anemia, Bloom’s syndrome, Kostmann’s syndrome, paroxysmal nocturnal hemoglobinuria, Li-Fraumeni syndrome, and neurofibromatosis are associated with a predisposition to development of AML. Exposure to drugs such as alkylating agents, epipodophyllotoxins, and nitrosoureas and to ionizing radiation are also associated with an increased risk of developing AML.

CLINICAL MANIFESTATIONS.

AML may present with signs and symptoms related to anemia, thrombocytopenia, or neutropenia. 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.

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 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 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 US: Each year, 2000-2500 new cases of childhood ALL are diagnosed. Internationally: Incidence is thought to be similar throughout the world.

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 PO tid

Pediatric Dose 40 mg/m2/d PO divided tid

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 PO divided tid

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; ofteot 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 iausea 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 PO bid 3 d/wk; alternatively 1 double-strength tab bid 3 d/wk

Pediatric Dose 5-10 mg/kg/d (based on trimethoprim component) PO divided q12h 3 times/wk

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 PO swish and swallow qid

Pediatric Dose 5 mL PO swish and swallow qid

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 PO qid

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 PO qd

Pediatric Dose 10 mg/kg/d PO

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 United States, with an annual incidence of 13.2 per million children.

                                                              

 

The two broad categories of lymphoma, Hodgkin’s disease and non-Hodgkin’s lymphoma (NHL) have such different clinical manifestations and treatments that they are considered separately.

 

Hodgkin’s Disease

Hodgkin’s disease accounts for about 5% of cancers in children and adolescents younger than 15 yr in the United States. This does not include the older adolescents who account for a substantial proportion of newly diagnosed patients. Although in industrialized countries the highest rate is in adolescents and young adults, in developing countries younger children are more frequently diagnosed.

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 1 — Ann Arbor Staging System for Hodgkin’s Disease*

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. The diagnostic work-up once the histologic diagnosis has been established. These studies should provide all the informatioeeded to clinically stage the disease based on the Ann Arbor classification.

 

TABLE 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

Chest CT with contrast

Abdominal CT with contrast

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. Chest CT more clearly defines the extent of a mediastinal mass if present and identifies hilar nodes and pulmonary parenchymal involvement, which may not be evident on chest radiographs. Abdominal CT scan can identify gross subdiaphragmatic involvement of nodes together with enlargement and defects in the liver and spleen. A gallium scan is particularly helpful in identifying areas of increased uptake, which can then be re-evaluated at the end of treatment, especially in patients with mediastinal masses that do not completely resolve on chest radiographs or CT. MRI has not been shown to increase the diagnostic precision of the evaluation. Lymphangiography, although unique in its ability to demonstrate intrinsic abnormalities in lymph nodes, is not without risk, is labor intensive and uncomfortable, and fails to visualize upper para-aortic nodes. It is rarely performed in pediatric practice, where systemic therapy has become the cornerstone of treatment and would be expected to eliminate relatively small foci of disease.

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 North America has evolved from primary treatment with extended-field radiation therapy to use of multiagent chemotherapy as the cornerstone of treatment, supplemented in selected cases, by relatively low-dose involved-field irradiation (2,000-2,500 cGy). Treatment is largely determined by disease stage, patient’s age at diagnosis, the presence or absence of B “symptoms,” and the presence of bulky nodal disease.

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.

 

Non-Hodgkin’s Lymphoma (NHL)

 

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 United States. In equatorial Africa, 50% of childhood cancers are lymphomas, a result of the very high incidence of Burkitt’s lymphoma. Unlike Hodgkin’s disease, the incidence of NHL increases steadily throughout life. In some situations there is overlap with acute lymphoblastic leukemia. Patients with lymphoblastic NHL and more than 25% lymphoblasts in the bone marrow are arbitrarily classified and treated as if they had ALL, whereas patients with B-cell ALL are treated similarly to patients with Burkitt’s lymphoma even if no extramedullary disease is present.

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 United States. How EBV contributes to the pathogenesis of Burkitt’s lymphoma remains unclear. Pre-existing immunodeficiency (congenital or acquired) also predisposes to the development of NHL.

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 U.S. cases with abdominal pain or distention, bowel obstruction, change in bowel habits, intestinal bleeding, or rarely intestinal perforation. Other sites include CNS, bone marrow, and peripheral lymph nodes. Jaw involvement occurs in less than 20% of U.S. cases, compared with 70% of younger patients in equatorial Africa.

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 3 lists the studies necessary to accurately stage the disease and provides baseline measurements of organ functioeeded 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 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 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 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.

 

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 France, immunophenotype-directed therapy is used for these cases.

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.

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.

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. 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.

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.

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. 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. 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.

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 38°C for 3 consecutive days

·                                 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 38°C for 3 consecutive days

·                                 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

·                                 Brucellosis

·                                 Catscratch Disease

·                                 Cytomegalovirus Infection

·                                 Histoplasmosis

·                                 Lymph Node Disorders

·                                 Mononucleosis and Epstein-Barr Virus Infection

·                                 Non-Hodgkin Lymphoma

·                                 Pediatric Histoplasmosis

·                                 Toxoplasmosis

·                                 Tuberculosis

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, 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.

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.

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 oormal 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, 19th Edition. – Expert Consult Premium Edition – Enhanced Online Features and Print / by Robert M. Kliegman, MD, Bonita M.D. Stanton, MD, Joseph St. Geme, Nina Schor, MD, PhD and Richard E. Behrman, MD. – 2011. – 2680 p.

2.     Hastings CA, Torkildson JC, Agrawal AK. Handbook of Pediatric Hematology and Oncology: Children’s Hospital and Research Center Oakland, second edition. Oxford, John Wiley & Sons, 2012. – 378p.

3.     Manual of Pediatric Hematology and Oncology, Fifth Edition. Edited by: Philip Lanzkowsky. Academic Press. – 1027p.

4.     Pediatrics / Edited by O.V. Tiazhka, T.V. Pochinok, A.M. Antoshkina/ – Vinnytsa: Nova Knyha Publishers, 2011. – 584 p.

 

WEB–adresses

http://www.emedicine.com

http://www.meadline

htttp;//www.babynet.at