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Home > Living Well > Health Library > Childhood Non-Hodgkin Lymphoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. For NHL, the 5-year survival rate increased over the same time period from about 45% to 90% for both younger children and adolescents.[1,2] In 2020, there were an estimated 30,500 survivors of childhood and adolescent NHL in the United States.
Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on the Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
On the basis of immunophenotype, molecular biology, and clinical response to treatment, most NHL cases occurring in childhood and adolescence fall into three categories:
Other rare types of pediatric NHL include the following:
Lymphoma (Hodgkin lymphoma and NHL) is the third most common childhood malignancy, and NHL accounts for approximately 7% of cancers in children younger than 20 years in high-income countries.
The following factors affect the incidence of NHL in children and adolescents:
In sub-Saharan Africa, the incidence of Epstein-Barr virus (EBV)–induced Burkitt lymphoma/leukemia is tenfold to twentyfold higher than the incidence in the United States, resulting in a much higher incidence of NHL.
The incidence of NHL is increasing overall because of a slight increase in the incidence for those aged 15 to 19 years. Conversely, the incidence of NHL in children younger than 15 years has remained constant over the past several decades.
The incidence and age distribution of histologic types of NHL according to sex is described in Table 1.
Relatively little data on the epidemiology of childhood NHL have been published. However, known risk factors include the following:
Unlike adults with NHL who present most often with nodal disease, children typically have extranodal disease involving the mediastinum, abdomen, and/or head and neck, as well as the bone marrow or CNS. In developed countries, Burkitt lymphoma/leukemia occurs in the abdomen in approximately 60% of cases, with 15% to 20% of cases arising in the head and neck.[13,14] This high incidence of extranodal disease substantiates the use of the Murphy staging system for pediatric NHL, instead of the Ann Arbor staging system.
The following tests and procedures are used to diagnose childhood NHL:
Prognosis and Prognostic Factors for Childhood NHL
In high-income countries and with current treatments, more than 80% of children and adolescents with NHL will survive at least 5 years, although outcome depends on a number of factors, including clinical stage and histology.
Prognostic factors for childhood NHL include the following:
Refer to the following sections of this summary for more information about the tumor biology and genomic alterations associated with each type of NHL, some of which are being evaluated as potential prognostic biomarkers:
Response to therapy
Response to therapy in pediatric lymphoma is one of the most important prognostic markers. Regardless of histology, pediatric NHL that is refractory to first-line therapy has a very poor prognosis,[16,17,18,19,20] with the exception of anaplastic large cell lymphoma.[16,21]
International pediatric NHL response criteria have been proposed but require prospective evaluation. The clinical utility of these new criteria are under investigation.
In contrast to the prognostic value of minimal residual disease (MRD) in patients with acute leukemia, the prognostic value of MRD after therapy is initiated remains uncertain and requires further investigation in pediatric patients with NHL.
Stage at diagnosis/minimal disseminated disease (MDD)
In general, patients with low-stage disease (i.e., single extra-abdominal/extrathoracic tumor or totally resected intra-abdominal tumor) have an excellent prognosis (5-year survival rate of approximately 90%), regardless of histology.[22,25,31,32,33] Apart from this finding, the outcome by clinical stage, using appropriate therapy on the basis of risk stratification, does not differ significantly.
A surrogate for tumor burden, specifically elevated levels of LDH, has been shown to be prognostic in many studies.[22,31,34]
MDD is generally defined as submicroscopic bone marrow involvement that is present at diagnosis. MDD is generally detected by sensitive methods such as flow cytometry or reverse transcription–polymerase chain reaction (RT-PCR). Patients with morphologically involved bone marrow with more than 5% lymphoma cells are considered to have stage IV disease.
An Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) study used an MDD cutoff level of 3% by flow cytometry. The study observed a 5-year EFS rate of 60% for patients with MDD greater than 3% versus 83% for the remaining patients (P = .04).
The largest experience with MDD for T-cell lymphoblastic lymphoma (n = 273) is from the COG AALL0434 (NCT00408005) study, in which MDD had no prognostic impact. Patients with bone marrow MDD levels of less than 1% had an EFS rate of 82.4% compared with 89.5% for those with MDD levels of 1% or higher (P = .3084).
The presence of MDD is significantly associated with uncommon histologic subtypes containing small cell and/or lymphohistiocytic components.
Sites of disease at diagnosis
In pediatric NHL, some sites of disease appear to have prognostic value, including the following:
NHL in infants is rare (1% in BFM trials from 1986 to 2002). In this retrospective review, the outcome for infants was inferior compared with the outcome for older patients with NHL.
Adolescents have been reported to have outcomes inferior to those of younger children.[13,15,54] This adverse effect of age appears to be most pronounced for adolescents with diffuse large B-cell lymphoma, and to a lesser degree, T-cell lymphoblastic lymphoma.[15,54] Conversely, for patients with Burkitt lymphoma/leukemia, adolescent age (≥15 years) was not an independent risk factor for inferior outcome.[24,34]
Immune response to tumor
An immune response against the ALK protein (i.e., anti-ALK antibody titer) appeared to correlate with lower clinical stage and predicted relapse risk but not OS. A study by the EICNHL, which combined the level of anti-ALK antibody with MDD, demonstrated that patients with newly diagnosed anaplastic large cell lymphoma could be stratified into three risk groups, with the following PFS rates:
In a cohort of Japanese patients with anaplastic large cell lymphoma who were treated on the ALCL99 (NCT00006455) study, comparable results were obtained for a three-category risk classification algorithm. For a cohort of 180 patients with anaplastic large cell lymphoma who were treated on several European studies, low anti-ALK antibody titer retained prognostic significance in a multivariate analysis, along with MDD, MRD, and uncommon histology (small cell and others).[Level of evidence: 2A]
In children, non-Hodgkin lymphoma (NHL) is distinct from the more common forms of lymphoma observed in adults. While lymphomas in adults are more commonly low or intermediate grade, almost all NHL that occurs in children is high grade.[1,2] The World Health Organization (WHO) classifies NHL according to the following features:
On the basis of the WHO classification, most NHL cases in childhood and adolescence fall into the following three categories:
Compared with treatments for adults, aggressive Burkitt regimens in pediatrics have been used to treat patients with both Burkitt lymphoma/leukemia and large B-cell histologies, resulting in no difference in outcome based on histology.[4,5,6,7,8] The exception is for patients with primary mediastinal B-cell lymphoma, who have had inferior outcomes with these regimens.[4,5,6,7,9]
For patients with pediatric Burkitt lymphoma/leukemia, secondary cytogenetic abnormalities, other than MYC rearrangement, have been associated with an inferior outcome,[10,11] and cytogenetic abnormalities involving gain of 7q or deletion of 13q may be associated with an inferior outcome on the FAB/LMB-96 chemotherapy protocol.[11,12] For pediatric patients with diffuse large B-cell lymphoma and chromosomal rearrangement at MYC (8q24), outcomes may be worse.
Results from the Inter-B-NHL Ritux 2010 (NCT01516580) phase III trial showed that the addition of rituximab to chemotherapy for patients with aggressive mature B-cell NHL improved event-free survival (EFS) rates, from 82% to 94%. The small number of treatment failures, resulting from a high EFS rate, make it challenging to confirm these previously identified candidate prognostic biomarkers.
LBCL-IRF4 is included in the WHO 2017 classification as a provisional entity. LBCL-IRF4 cases have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci and has been associated with a favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this finding.[14,15]
Refer to the Tumor biology (Genomics of Burkitt lymphoma/leukemia), Tumor biology (Genomics of diffuse large B-cell lymphoma), and Tumor biology (Genomics of primary mediastinal B-cell lymphoma) sections of this summary for more information about the tumor biology and genomic alterations.
Refer to the Tumor Biology (Genomics of lymphoblastic lymphoma) section of this summary for more information about the tumor biology and genomic alterations.
In adults, ALK-negative disease has an inferior outcome; however, in children, the difference in outcome between ALK-positive and ALK-negative disease has not been demonstrated.[16,17,18] In a series of 375 children and adolescents with systemic ALK-positive anaplastic large cell lymphoma enrolled on the ALCL99 (NCT00006455) study, the presence of a small cell or lymphohistiocytic component was observed in 32% of patients and was significantly associated with a high risk of failure in the multivariate analysis, controlling for clinical characteristics. With longer follow-up, presence of the small cell/lymphohistiocytic pattern maintained its prognostic significance on multivariate analysis.
In the COG-ANHL0131 (NCT00059839) study, despite a different chemotherapy backbone, patients with the small cell variant of anaplastic large cell lymphoma, as well as other histologic variants, had a significantly increased risk of failure.
Refer to the Tumor Biology (Genomics of anaplastic large cell lymphoma) section of this summary for more information about the tumor biology and genomic alterations.
WHO Classification for NHL
The WHO classification is the most widely used NHL classification and is shown in Table 2, with immunophenotype and common clinical and molecular findings in pediatric NHL.[1,2]
Other types of lymphoma, such as the nonanaplastic large cell peripheral T-cell lymphomas (including T/NK lymphomas), cutaneous lymphomas, and indolent B-cell lymphomas (e.g., follicular lymphoma and marginal zone lymphoma), are more commonly seen in adults and rarely occur in children. The most recent WHO classification has designated pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma as distinct entities from the counterparts observed in adults.
Refer to the following PDQ summaries for more information about the treatment of NHL in adult patients:
The Ann Arbor staging system is used for all lymphomas in adults and for Hodgkin lymphoma in pediatrics. However, the Ann Arbor staging system has less prognostic value in pediatric non-Hodgkin lymphoma (NHL), primarily because of the high incidence of extranodal disease. Therefore, the most widely used staging schema for childhood NHL is that of the St. Jude Children's Research Hospital (Murphy Staging). A new staging system defines bone marrow and central nervous system (CNS) involvement using modern techniques to document the presence of malignant cells. However, the basic definitions of bone marrow and CNS disease are essentially the same. The clinical utility of this staging system is under investigation.
Role of Radiographic Imaging in Childhood NHL
Radiographic imaging is essential in the staging of patients with NHL. Ultrasonography may be the preferred method for assessment of an abdominal mass, but computed tomography (CT) scan and magnetic resonance imaging (MRI) have been used for staging.
The role of functional imaging in pediatric NHL is evolving and still being refined. Gallium scans have been replaced by fluorine F 18-fludeoxyglucose positron emission tomography (PET) scanning, which is now routinely performed at many centers. A review of the revised International Workshop Criteria comparing CT imaging alone or CT together with PET imaging demonstrated that the combination of CT and PET imaging was more accurate than CT imaging alone.[4,5]
While the International Working Group (formerly called the International Harmonization Project for PET) response criteria have been attempted in adults, the prognostic value of PET scanning for staging pediatric NHL remains under investigation.[3,6,7] Data support that PET identifies more abnormalities than does CT scanning, but it is unclear whether this should be used to upstage pediatric patients and change therapy. The International Working Group has updated their response criteria for malignant lymphoma to include PET, immunohistochemistry, and flow cytometry data.[5,9]
St. Jude Children's Research Hospital (Murphy) Staging
Stage I childhood NHL
In stage I childhood NHL, a single tumor or nodal area is involved, excluding the abdomen and mediastinum.
Stage II childhood NHL
In stage II childhood NHL, disease extent is limited to a single tumor with regional node involvement, two or more tumors or nodal areas involved on one side of the diaphragm, or a primary gastrointestinal tract tumor (completely resected) with or without regional node involvement.
Stage III childhood NHL
In stage III childhood NHL, tumors or involved lymph node areas occur on both sides of the diaphragm. Stage III NHL also includes any primary intrathoracic (mediastinal, pleural, or thymic) disease, extensive primary intra-abdominal disease, or any paraspinal or epidural tumors.
Stage IV childhood NHL
In stage IV childhood NHL, tumors involve the bone marrow and/or CNS, regardless of other sites of involvement.
Bone marrow involvement has been defined as 5% or more malignant cells in an otherwise normal bone marrow, with normal peripheral blood counts and smears. Patients with lymphoblastic lymphoma who have more than 25% malignant cells in the bone marrow are usually considered to have leukemia and may be appropriately treated on leukemia clinical trials.
CNS disease in lymphoblastic lymphoma is defined by criteria similar to that used for acute lymphocytic leukemia (i.e., white blood cell count of at least 5/μL and malignant cells in the cerebrospinal fluid [CSF]). For other types of NHL, the definition of CNS disease is any malignant cell present in the CSF regardless of cell count. The Berlin-Frankfurt-Münster group analyzed the prevalence of CNS involvement in NHL in more than 2,500 patients. Overall, CNS involvement was diagnosed in 6% of patients. CNS involvement (percentage of patients) according to NHL subtype was as follows:
Many of the improvements in childhood cancer survival have been made by employing combinations of known and/or new agents aimed at improving the best available, accepted therapy. Clinical trials in pediatrics are designed to compare potentially better therapy with therapy that is currently accepted as standard. This comparison may be done in a randomized study of two treatment arms or by evaluating a single new treatment and comparing the results with those previously obtained with standard therapy.
All children with non-Hodgkin lymphoma (NHL) should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists with experience treating tumors of childhood is strongly recommended to determine, coordinate, and implement treatment to achieve optimal survival. Children with NHL should be referred for treatment by a multidisciplinary team of pediatric oncologists at an institution with experience in treating pediatric cancers. Information about ongoing National Cancer Institute (NCI)–supported clinical trials is available from the NCI website.
NHL in children is generally considered to be widely disseminated at diagnosis, even when the tumor is apparently localized; as a result, combination chemotherapy is recommended for most patients. Exceptions to this treatment strategy include the following:
In contrast to the treatment of adults with NHL, the use of radiation therapy is limited in children with NHL. Study results include the following:
Radiation therapy may have a role in treating patients who have not had a complete response to chemotherapy. Data to support limiting the use of radiation therapy in the treatment of pediatric NHL come from the Childhood Cancer Survivor Study. This analysis demonstrated that radiation exposure was a significant risk factor for subsequent neoplasms and death in long-term survivors.
The treatment of NHL in childhood and adolescence has historically been based on the histologic subtype of the disease. A study by the Children's Cancer Group demonstrated that the outcomes for patients with lymphoblastic lymphoma were superior with longer acute lymphoblastic leukemia–like therapy, while patients with nonlymphoblastic NHL (Burkitt lymphoma/leukemia) had superior outcomes with short, intensive, pulsed therapy; the outcomes for patients with large cell lymphoma were similar with either approach.
Outcomes for children and adolescents with recurrent NHL remain very poor, with the exception of patients with anaplastic large cell lymphoma.[9,10,11,12,13,14] Patients or families who desire additional disease-directed therapy should consider entering trials of novel therapeutic approaches. Regardless of whether a decision is made to pursue disease-directed therapy at the time of progression, palliative care remains a central focus of management. This ensures that quality of life is maximized while attempting to reduce symptoms and stress related to the terminal illness.
Table 3 describes the treatment options for newly diagnosed and recurrent childhood NHL.
The most common potentially life-threatening clinical situations, seen most frequently in patients with lymphoblastic lymphoma and Burkitt lymphoma/leukemia, are the following:
Patients with large mediastinal masses are at risk of tracheal compression, superior vena caval compression, large pleural and pericardial effusions, and right and left ventricular outflow compression. Thus, cardiac or respiratory arrest is a significant risk, particularly if the patient is placed in a supine position for procedures such as computed tomography (CT) scans or echocardiograms. Most of these procedures can be performed with patients on their side or prone.
Because of the risk of complications from general anesthesia or heavy sedation, a careful physiologic and radiographic evaluation of the patient should be completed, and the least invasive procedure should be used to establish the diagnosis of lymphoma.[16,17] The following procedures may be used:
In situations when the above procedures do not yield a diagnosis, the use of a CT-guided core-needle biopsy should be considered. This procedure can frequently be performed using light sedation and local anesthesia before more invasive procedures are undertaken. Care should be taken to keep patients out of a supine position. Mediastinoscopy, anterior mediastinotomy, or thoracoscopy are the procedures of choice when other diagnostic modalities fail to establish the diagnosis. A formal thoracotomy is rarely, if ever, indicated for the diagnosis or treatment of childhood lymphoma.
Occasionally, it will not be possible to perform a diagnostic operative procedure because of the risk of complications from general anesthesia or heavy sedation. In these situations, preoperative treatment with steroids or, less commonly, localized radiation therapy should be considered. Because preoperative treatment may affect the ability to obtain an accurate tissue diagnosis, a diagnostic biopsy should be done as soon as the risk of complications from general anesthesia or heavy sedation is reduced.
Tumor lysis syndrome
Tumor lysis syndrome results from rapid breakdown of malignant cells, causing several metabolic abnormalities, most notably hyperuricemia, hyperkalemia, and hyperphosphatemia. Patients may present with tumor lysis syndrome before the start of therapy.
Hyperhydration and allopurinol or rasburicase (urate oxidase) are essential components of therapy in all patients, except those with the most limited disease.[19,20,21,22,23,24] In patients with G6PD deficiency, rasburicase may cause hemolysis or methemoglobinuria and should be avoided. An initial prephase consisting of low-dose cyclophosphamide and vincristine does not obviate the need for allopurinol or rasburicase and hydration.
Hyperuricemia and tumor lysis syndrome, particularly when associated with ureteral obstruction, frequently result in life-threatening complications.
Although the use of positron emission tomography (PET) to assess rapidity of response to therapy appears to have prognostic value in Hodgkin lymphoma and some types of NHL observed in adult patients, it remains under investigation in pediatric NHL. To date, there are insufficient data for pediatric NHL to support a finding that early response to therapy assessed by PET has prognostic value.
Diagnosing relapsed disease solely on the basis of imaging requires caution because false-positive results are common.[25,26,27,28] Data also demonstrate that PET scanning can produce false-negative results. A study of young adults with primary mediastinal B-cell lymphoma demonstrated that 9 of 12 patients who had residual mediastinal masses at the end of therapy had positive PET scans. Seven of these nine patients had the masses resected, but no viable tumor was found. Before changes in therapy are undertaken on the basis of residual masses noted by imaging, even if the PET scan is positive, a biopsy to prove residual disease is warranted.
Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive the treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer. At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with current standard therapy. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing NCI-supported clinical trials is available from the NCI website.
In the United States, Burkitt lymphoma/leukemia accounts for about 40% of childhood non-Hodgkin lymphoma (NHL) cases and exhibits a consistent, aggressive clinical behavior.[1,2] The overall incidence of Burkitt lymphoma/leukemia in the United States is 2.5 cases per 1 million person-years and is higher among boys than girls (3.9 vs. 1.1).[2,3] (Refer to Table 1 for more information about the incidence of Burkitt lymphoma by age and sex distribution.)
The most common primary sites of disease are the abdomen and the lymphatic tissue of Waldeyer ring. Other sites of involvement include testes, bone, skin, bone marrow, and central nervous system (CNS). While lung involvement does not tend to occur, pleural and peritoneal spread are seen.
Genomics of Burkitt lymphoma/leukemia
The malignant cells of Burkitt lymphoma/leukemia show a mature B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase. These malignant cells usually express surface immunoglobulin (Ig), most bearing a clonal surface IgM with either kappa or lambda light chains. A variety of additional B-cell markers (e.g., CD19, CD20, CD22) are usually present, and most childhood Burkitt lymphomas/leukemias express CD10.
Burkitt lymphoma/leukemia expresses a characteristic chromosomal translocation, usually t(8;14) and more rarely t(8;22) or t(2;8). Each of these translocations juxtaposes the MYC oncogene and the immunoglobulin locus (IG, mostly the IGH locus) regulatory elements, resulting in the inappropriate expression of MYC, a gene involved in cellular proliferation.[5,6,7] The presence of one of the variant translocations t(2;8) or t(8;22) does not appear to affect response or outcome.[8,9]
Mapping of IGH-translocation breakpoints demonstrated that IG-MYC translocations in sporadic Burkitt lymphoma most commonly occur through aberrant class-switch recombination and less commonly through somatic hypermutation; translocations resulting from aberrant variable, diversity, and joining (VDJ) gene segment recombinations are rare. These findings are consistent with a germinal center derivation of Burkitt lymphoma.
While MYC translocations are present in all Burkitt lymphoma, cooperating genomic alterations appear to be required for lymphoma development. Some of the more commonly observed recurring mutations that have been identified in Burkitt lymphoma in pediatric and adult cases are listed below. The clinical significance of these mutations for pediatric Burkitt lymphoma remains to be elucidated.
A study that compared the genomic landscape of endemic Burkitt lymphoma with the genomics of sporadic Burkitt lymphoma found the expected high rate of Epstein-Barr virus (EBV) positivity in endemic cases, with much lower rates in sporadic cases. There was general similarity between the patterns of mutations for endemic and sporadic cases and for EBV-positive and EBV-negative cases; however, EBV-positive cases showed significantly lower mutation rates for selected genes/pathways, including SMARCA4, CCND3, TP53, and apoptosis.
Cytogenetic evidence of MYC rearrangement is the gold standard for diagnosis of Burkitt lymphoma/leukemia. For cases in which cytogenetic analysis is not available, the World Health Organization (WHO) has recommended that the Burkitt-like diagnosis be reserved for lymphoma resembling Burkitt lymphoma/leukemia or with more pleomorphism, large cells, and a proliferation fraction (i.e., MIB-1 or Ki-67 immunostaining) of 99% or greater. BCL2 staining by immunohistochemistry is variable. The absence of a translocation involving the BCL2 gene does not preclude the diagnosis of Burkitt lymphoma/leukemia and has no clinical implications.
Genomics of Burkitt-like lymphoma with 11q aberration
Burkitt-like lymphoma with 11q aberration was added as a provisional entity in the 2017 revised WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. In this entity, MYC rearrangement is absent, and the characteristic chromosome 11q finding (detected cytogenetically and/or with copy-number DNA arrays) is 11q23.2-q23.3 gain/amplification and 11q24.1-qter loss.[18,19]
Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information about prognostic factors for Burkitt lymphoma/leukemia.
Standard treatment options for Burkitt lymphoma/leukemia
The treatment of Burkitt lymphoma/leukemia is the same as treatment for diffuse large B-cell lymphoma, and the following discussion is pertinent to both types of childhood NHL.
Unlike mature B-lineage NHL seen in adult patients, there is no difference in outcome based on histology in pediatric patients (Burkitt lymphoma/leukemia or diffuse large B-cell lymphoma). Pediatric Burkitt lymphoma/leukemia and diffuse large B-cell lymphoma are clinically very aggressive, and patients are treated with very intensive regimens.[21,22,23,24,25,26]
Tumor lysis syndrome is often present at diagnosis or after initiation of treatment. This emergent clinical situation should be anticipated and addressed before treatment is started. (Refer to the Tumor lysis syndrome section in the Treatment Option Overview for Childhood NHL section of this summary for more information.)
Current treatment strategies are based on risk stratification, as described in Table 4. Involvement of the bone marrow may lead to confusion about whether the patient has lymphoma or leukemia. Traditionally, patients with more than 25% marrow blasts are classified as having mature B-cell leukemia, and those with fewer than 25% marrow blasts are classified as having lymphoma. It is not clear whether these arbitrary definitions are biologically distinct, but there is no question that patients with Burkitt leukemia should be treated with protocols designed for Burkitt lymphoma.[21,23,26]
The following studies have contributed to the development of current treatment regimens for pediatric patients with Burkitt lymphoma/leukemia and diffuse large B-cell lymphoma.
Both the BFM and FAB/LMB studies demonstrated that omission of craniospinal irradiation, even in patients presenting with CNS disease, does not affect outcome (COG-C5961 [FAB/LMB-96] and NHL-BFM-90 [GER-GPOH-NHL-BFM-90]).[21,22,23,28]
Standard treatment options for Burkitt lymphoma/leukemia and diffuse large B-cell lymphoma are described in Table 5.
Treatment options for recurrent or refractory Burkitt lymphoma/leukemia
There is no standard treatment option for patients with recurrent or progressive disease. For patients with recurrent or refractory aggressive mature B-cell NHL, reported survival ranges between 10% to 50%; in the largest series, survival was reported to be about 20%.[23,31,32]; [Level of evidence: 3iiiA] Three large retrospective multivariable analyses identified the following prognostic factors:
Treatment options for recurrent or refractory Burkitt lymphoma/leukemia and diffuse large B-cell lymphoma include the following:
Chemoresistance makes remission difficult to achieve.
Evidence (treatment of recurrent or refractory Burkitt lymphoma/leukemia):
If remission can be achieved, high-dose therapy plus SCT remains the best option for survival. Patients not in remission at the time of transplant fare significantly worse.[34,37,42,44,45,46] The very poor outcome of patients whose disease is refractory to salvage chemotherapy suggests that a nonexperimental transplant option should not be pursued in these patients.[37,45,46] If a complete remission was reported, survival ranges between 30% to 75%, albeit all series have a small number of patients (i.e., fewer than 40).[37,42,43,45,47] The benefit of autologous versus allogeneic SCT remains unclear.[32,37,47,48]; [Level of evidence: 2A]; [Level of evidence: 3iiiDii]
(Refer to the PDQ summaries on Pediatric Autologous Hematopoietic Stem Cell Transplantation, Pediatric Allogeneic Hematopoietic Stem Cell Transplantation, and Pediatric Hematopoietic Stem Cell Transplantation and Cellular Therapy for Cancer for more information about transplantation).
Evidence (SCT therapy):
Treatment options under clinical evaluation for Burkitt leukemia/lymphoma
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Diffuse Large B-cell Lymphoma
Primary mediastinal B-cell lymphoma, previously considered a subtype of diffuse large B-cell lymphoma, is now a separate entity in the most recent WHO classification. (Refer to the Primary Mediastinal B-cell Lymphoma section of this summary for more information.)
Diffuse large B-cell lymphoma is an aggressive mature B-cell neoplasm that represents 10% to 20% of pediatric NHL cases.[2,50] Diffuse large B-cell lymphoma occurs more frequently during the second decade of life than during the first decade.[2,51] (Refer to Table 1 for more information on the incidence of diffuse large B-cell lymphoma by age and sex distribution.)
Pediatric diffuse large B-cell lymphoma may present in a manner clinically similar to that of Burkitt lymphoma/leukemia, although more often it is localized, and less often it involves the bone marrow or CNS.[50,51] (Refer to the Clinical presentation section in the Burkitt Lymphoma/Leukemia section of this summary for more information.)
Genomics of diffuse large B-cell lymphoma
The World Health Organization (WHO) classification system categorizes diffuse large B-cell lymphoma on the basis of molecular characteristics into the germinal center B-cell subtype and the activated B-cell subtype, with the remaining types being classified as diffuse large B-cell lymphoma, not otherwise specified (NOS).
Diffuse large B-cell lymphoma in children and adolescents differs biologically from diffuse large B-cell lymphoma in adults in the following ways:
Large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) was added as a provisional entity in the 2017 revision of the WHO classification of lymphoid neoplasms.
High-grade B-cell lymphoma, NOS is defined as a clinically aggressive B-cell lymphoma that lacks MYC plus BCL2 and/or BCL6 rearrangements and that does not meet criteria for diffuse large B-cell lymphoma, NOS or Burkitt lymphoma.
Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information about prognostic factors for diffuse large B-cell lymphoma.
Treatment options for diffuse large B-cell lymphoma
As with Burkitt lymphoma/leukemia, current treatment strategies are based on risk stratification, as described in Table 5. The treatment of diffuse large B-cell lymphoma is the same as the treatment of Burkitt lymphoma/leukemia. Refer to the Standard treatment options for Burkitt lymphoma/leukemia section of this summary for information about the treatment of diffuse large B-cell lymphoma.
Treatment options for recurrent or refractory diffuse large B-cell lymphoma
The treatment of recurrent diffuse large B-cell lymphoma is the same as the treatment of recurrent Burkitt lymphoma/leukemia. Refer to the Treatment options for recurrent or refractory Burkitt lymphoma/leukemia section of this summary for more information.
Treatment options under clinical evaluation for diffuse large B-cell lymphoma
Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
Primary Mediastinal B-cell Lymphoma
In the pediatric population, primary mediastinal B-cell lymphoma is predominantly seen in older adolescents, accounting for 1% to 2% of all pediatric NHL cases.[51,65,66,67]
As the name suggests, primary mediastinal B-cell lymphoma occurs in the mediastinum. The tumor can be locally invasive (e.g., pericardial and lung extension) and can be associated with superior vena cava syndrome. The tumor can disseminate outside the thoracic cavity with nodal and extranodal involvement, with predilection to the kidneys; however, CNS and marrow involvement are exceedingly rare.
Genomics of primary mediastinal B-cell lymphoma
Primary mediastinal B-cell lymphoma was previously considered a subtype of diffuse large B-cell lymphoma, but is now a separate entity in the most recent World Health Organization (WHO) classification. These tumors arise in the mediastinum from thymic B-cells and show a diffuse large cell proliferation with sclerosis that compartmentalizes neoplastic cells.
Primary mediastinal B-cell lymphoma can be very difficult to distinguish morphologically from the following types of lymphoma:
Primary mediastinal B-cell lymphoma has distinctive gene expression and mutation profiles compared with diffuse large B-cell lymphoma; however, its gene expression and mutation profiles have features similar to those seen in Hodgkin lymphoma.[70,71,72] Primary mediastinal B-cell lymphoma is also associated with a distinctive constellation of chromosomal aberrations compared with other NHL subtypes. Because primary mediastinal B-cell lymphoma is primarily a cancer of adolescents and young adults, the genomic findings are presented without regard to age.
Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information on prognostic factors for primary mediastinal B-cell lymphoma.
Treatment options for primary mediastinal B-cell lymphoma
Treatment options for primary mediastinal B-cell lymphoma include the following:
Pediatric and adolescent patients with stage III primary mediastinal large B-cell lymphoma fared significantly worse on the FAB/LMB-96 (NCT00002757) study, with a 5-year EFS rate of 66%, compared with 85% for adolescents with nonmediastinal diffuse large B-cell lymphoma.[Level of evidence: 2A] Similarly, in the NHL-BFM-95 trial, patients with primary mediastinal B-cell lymphoma had an EFS rate of 50% at 3 years. However, a study of young adults treated with DA-EPOCH-R showed excellent disease-free survival rates.
Treatment options for recurrent or refractory primary mediastinal B-cell lymphoma
The U.S. Food and Drug Administration granted accelerated approval of pembrolizumab for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma or who have relapsed after two or more previous lines of therapy. The approval was based on data from 53 patients (median age, 33 years; range, 20–61 years). The overall response rate was 41%, which included 12% complete responses and 29% partial responses.
Treatment options under clinical evaluation for primary mediastinal B-cell lymphoma
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Lymphoblastic lymphoma comprises approximately 20% of childhood non-Hodgkin lymphoma (NHL) cases.[1,2] (Refer to Table 1 for more information about the incidence of lymphoblastic lymphoma by age and sex distribution.)
As many as 75% of patients with T-cell lymphoblastic lymphoma will present with an anterior mediastinal mass, which may manifest as dyspnea, wheezing, stridor, dysphagia, or swelling of the head and neck.
Pleural and/or pericardial effusions may be present, and the involvement of lymph nodes, usually above the diaphragm, may be a prominent feature. There may also be involvement of bone, skin, bone marrow, central nervous system (CNS), abdominal organs (but rarely bowel), and occasionally other sites, such as lymphoid tissue of Waldeyer ring, testes, or subcutaneous tissue. Abdominal involvement is less common in T-cell lymphoblastic lymphoma than in Burkitt lymphoma/leukemia.
Involvement of the bone marrow may lead to confusion about whether the patient has lymphoma with bone marrow involvement or leukemia with extramedullary disease. Traditionally, patients with more than 25% marrow blasts are considered to have T-cell acute lymphoblastic leukemia (ALL), and those with fewer than 25% marrow blasts are considered to have stage IV T-cell lymphoblastic lymphoma. The World Health Organization (WHO) classifies lymphoblastic lymphoma as the same disease as ALL. The debate centers on whether they truly represent the same disease. It is not yet clear whether these arbitrary definitions are biologically distinct or relevant for treatment design.
Genomics of lymphoblastic lymphoma
Lymphoblastic lymphomas are usually positive for terminal deoxynucleotidyl transferase, with more than 75% of cases having a T-cell immunophenotype and the remaining cases having a precursor B-cell phenotype.
As opposed to pediatric T-cell acute lymphoblastic leukemia (T-ALL), chromosomal abnormalities and the molecular biology of pediatric lymphoblastic lymphoma are not as well characterized. Many genomic alterations that occur in T-ALL also occur in T-cell lymphoblastic lymphoma. Examples include the following:
For the genomic alterations described above, NOTCH1 and FBXW7 mutations may confer a more favorable prognosis for patients with T-cell lymphoblastic lymphoma, while loss of heterozygosity at chromosome 6q, PTEN mutations, and KMT2D mutations may be associated with an inferior prognosis.[7,8,9,10,11] For example, one study noted that the presence of a KMT2D and/or PTEN mutation was associated with a high risk of relapse in patients with wild-type NOTCH1/FBXW7, but these mutations were not associated with an increased risk of relapse in patients with mutations in NOTCH1 or FBXW7. Studies with larger numbers of patients are needed to better define the critical genomic determinants of outcome for patients with T-cell lymphoblastic lymphoma.
There have been few studies of the genomic characteristics of B-lymphoblastic lymphoma. A report describing copy number alterations for pediatric B-lymphoblastic lymphoma cases noted that some gene deletions that are common in B-ALL (e.g., CDKN2A, IKZF1, and PAX5) appeared to occur with appreciable frequency in B-lymphoblastic lymphoma.
Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information about prognostic factors for lymphoblastic lymphoma.
Standard Treatment Options for Lymphoblastic Lymphoma
Low-stage (stage I or stage II) lymphoblastic lymphoma is primarily a B-cell disease. Treatment with short, pulsed chemotherapy (i.e., doxorubicin, cyclophosphamide, vincristine, and prednisone [CHOP]), followed by 6 months of maintenance therapy, produces a disease-free survival (DFS) rate of about 60% and an overall survival (OS) rate exceeding 90%.[12,13] However, the use of an ALL treatment approach, consisting of induction, consolidation, and maintenance therapy for a total of 24 months, has produced DFS rates higher than 90% in children with low-stage lymphoblastic lymphoma.[14,15,16]
Patients with high-stage (stage III or stage IV) lymphoblastic lymphoma have DFS rates higher than 80%.[14,15,17] Mediastinal involvement is common, but radiation therapy is not necessary for patients with mediastinal masses, except in the emergency treatment of symptomatic superior vena cava obstruction or airway obstruction. In these cases, either corticosteroid therapy or low-dose radiation therapy is usually employed. (Refer to the Mediastinal masses section of the Treatment Option Overview for Childhood NHL section of this summary for more information.)
The following studies have contributed to the development of current treatment regimens for pediatric patients with lymphoblastic lymphoma.
The Pediatric Oncology Group conducted a trial to test the effectiveness of high-dose methotrexate in the treatment of patients with T-cell ALL and T-cell lymphoblastic lymphoma. In the lymphoma patients (n = 66), high-dose methotrexate did not demonstrate a benefit, with a 5-year event-free survival (EFS) rate of 88%.[Level of evidence: 1iiA] Of note, all of these patients received prophylactic cranial radiation therapy, even though other studies have shown that it is not required for patients with T-cell lymphoblastic lymphoma.[15,17] In this study, the benefit of adding the cardioprotectant dexrazoxane was tested in a randomized fashion. The addition of dexrazoxane did not affect patient outcomes, and it provided cardioprotective benefits, as demonstrated by echocardiographic and laboratory assessments.[Level of evidence: 2A]
In the NHL-BFM-90 study, the 5-year DFS rate was 90%, and there was no difference in outcome between patients with stage III and stage IV disease. Patients with precursor B-cell lymphoblastic lymphoma appeared to have similar results using the same therapy. All patients received prophylactic cranial radiation therapy. In the NHL-BFM-95 study, the amount of daunorubicin and asparaginase in induction was reduced and patients did not receive prophylactic cranial radiation therapy. The DFS rate in this study was similar to the rate in the NHL-BFM-90 study; however, the EFS rate was lower, at 82%, because of a higher incidence of subsequent neoplasms. A single-center study reported that patients treated for lymphoblastic lymphoma had a higher incidence of subsequent neoplasms than did patients treated for other pediatric NHL. However, studies from the Children's Oncology Group (COG) and the Childhood Cancer Survivor Study Group did not support this finding.[17,21,22,23]
Evidence for chemotherapy (low-stage treatment regimens for lymphoblastic lymphoma):
Evidence for chemotherapy (high-stage treatment regimens for lymphoblastic lymphoma):
Equivalent outcomes were observed for patients treated on arms A1, B1, A2, and B2. The 5-year EFS rates were 81%, 80%, 84%, and 80%, respectively. The OS rates were 84%, 88%, 85%, and 85%, respectively. Patients with CNS disease at diagnosis had a 5-year EFS rate of 63% and an OS rate of 81%.
Treatment Options for Recurrent or Refractory Lymphoblastic Lymphoma
For patients with recurrent or refractory lymphoblastic lymphoma, reports of survival range from 10% to 40%.[21,24]; [Level of evidence: 2A]; [26,27][Level of evidence: 3iiiA] As in patients with Burkitt lymphoma/leukemia, chemoresistant disease is common.
There are no standard treatment options for patients with recurrent or refractory disease.
Treatment options for recurrent or refractory lymphoblastic lymphoma include the following:
Evidence (treatment of recurrent or refractory lymphoblastic lymphoma):
Treatment Options Under Clinical Evaluation for Lymphoblastic Lymphoma
Anaplastic large cell lymphoma accounts for approximately 10% of childhood non-Hodgkin lymphoma (NHL) cases. (Refer to Table 1 for more information about the incidence of anaplastic large cell lymphoma by age and sex distribution.)
Clinically, systemic anaplastic large cell lymphoma has a broad range of presentations. These include involvement of lymph nodes and a variety of extranodal sites, particularly skin and bone and, less often, gastrointestinal tract, lung, pleura, and muscle. Involvement of the central nervous system (CNS) and bone marrow is uncommon.
Anaplastic large cell lymphoma is often associated with systemic symptoms (e.g., fever, weight loss) and a prolonged waxing and waning course, making diagnosis difficult and often delayed. Patients with anaplastic large cell lymphoma may present with signs and symptoms consistent with hemophagocytic lymphohistiocytosis.
There is a subgroup of anaplastic large cell lymphoma patients who have leukemic peripheral blood involvement. These patients usually exhibit significant respiratory distress with diffuse lung infiltrates or pleural effusions and have hepatosplenomegaly.[3,4]
Genomics of anaplastic large cell lymphoma
While the predominant immunophenotype of anaplastic large cell lymphoma is mature T cell, null-cell disease (i.e., no T-cell, B-cell, or natural killer-cell surface antigen expression) does occur. The World Health Organization (WHO) classifies anaplastic large cell lymphoma as a subtype of peripheral T-cell lymphoma.
All anaplastic large cell lymphoma cases are CD30-positive. More than 90% of pediatric anaplastic large cell lymphoma cases have a chromosomal rearrangement involving the ALK gene. About 85% of these chromosomal rearrangements will be t(2;5)(p23;q35), leading to the expression of the fusion protein NPM-ALK; the other 15% of cases are composed of variant ALK translocations. Anti-ALK immunohistochemical staining pattern is quite specific for the type of ALK translocation. Cytoplasm and nuclear ALK staining is associated with NPM-ALK fusion protein, whereas cytoplasmic staining of ALK is only associated with the variant ALK translocations, as shown in Table 6.
In adults, ALK-positive anaplastic large cell lymphoma is viewed differently from other peripheral T-cell lymphomas because prognosis tends to be superior. Also, adult patients with ALK-negative anaplastic large cell lymphoma have an inferior outcome compared with patients who have ALK-positive disease. In children, however, this difference in outcome between ALK-positive and ALK-negative disease has not been demonstrated. In addition, no correlation has been found between outcome and the specific ALK-translocation type.[10,11,12]
In a European series of 375 children and adolescents with systemic ALK-positive anaplastic large cell lymphoma, the presence of a small cell or lymphohistiocytic component was observed in 32% of patients and was significantly associated with a high risk of failure in the multivariate analysis, controlling for clinical characteristics (hazard ratio, 2.0; P = .002). The prognostic implication of the small cell variant of anaplastic large cell lymphoma was also shown in the COG-ANHL0131 (NCT00059839) study, despite a different chemotherapy backbone.
Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information on prognostic factors for anaplastic large cell lymphoma.
Standard Treatment Options for Anaplastic Large Cell Lymphoma
Children and adolescents with high-stage (stage III or IV) anaplastic large cell lymphoma have a disease-free survival rate of approximately 60% to 75%.[13,14,15,16,17,18]
It is unclear which treatment strategy is best for patients with anaplastic large cell lymphoma. Current data do not suggest superiority of one treatment regimen over another for these standard treatment options.
Commonly used treatment regimens include the following:
Evidence (treatment of anaplastic large cell lymphoma):
CNS involvement in patients with anaplastic large cell lymphoma is rare at diagnosis. In an international study of systemic childhood anaplastic large cell lymphoma, 12 of 463 patients (2.6%) had CNS involvement, 3 of whom had isolated CNS disease (primary CNS lymphoma). For the CNS-positive group who received multiagent chemotherapy, including high-dose methotrexate, cytarabine, and intrathecal treatment, the EFS rate was 50% (95% confidence interval [CI], 25%–75%), and the OS rate was 74% (95% CI, 45%–91%) at a median follow-up of 4.1 years. The role of cranial radiation therapy has been difficult to assess.
Treatment Options for Recurrent or Refractory Anaplastic Large Cell Lymphoma
Unlike mature B-cell or lymphoblastic lymphoma, the survival rates for patients with recurrent or refractory anaplastic large cell lymphoma is 40% to 60%.[25,26,27,28]
There is no standard approach for the treatment of recurrent or refractory anaplastic large cell lymphoma.
Treatment options for recurrent or refractory anaplastic large cell lymphoma include the following:
Although remissions can be achieved with single-agent therapy (e.g., vinblastine, brentuximab, or crizotinib), CNS progressions after therapy have been observed in patients with recurrent anaplastic large cell lymphoma. In one series, four of five patients who developed CNS progressions achieved complete remissions with either radiation therapy or high-dose methotrexate.
Chemotherapy, followed by autologous SCT or allogeneic SCT, if remission can be achieved, has been employed in this setting.[26,27,36,37,40]
Evidence (chemotherapy and targeted therapy):
Evidence (autologous vs. allogeneic SCT):
Treatment Options Under Clinical Evaluation for Anaplastic Large Cell Lymphoma
The incidence of lymphoproliferative disease or lymphoma is 100-fold higher in immunocompromised children than in the general population. The causes of such immune deficiencies include the following:
Non-Hodgkin lymphoma (NHL) associated with immunodeficiency is usually aggressive, with most cases occurring in extralymphatic sites and a higher incidence of primary central nervous system (CNS) involvement.[1,2,3,4]
Lymphoproliferative Disease Associated With Primary Immunodeficiency
Lymphoproliferative disease observed in primary immunodeficiency usually shows an aggressive mature B-cell phenotype and large cell histology. Mature T-cell lymphoma and anaplastic large cell lymphoma have been observed. Children with primary immunodeficiency and NHL are more likely to have high-stage disease and present with symptoms related to extranodal disease, particularly in the gastrointestinal tract and CNS.
Treatment options for lymphoproliferative disease associated with primary immunodeficiency
Treatment options for lymphoproliferative disease associated with primary immunodeficiency include the following:
Patients with primary immunodeficiency can achieve complete and durable remissions with standard chemotherapy regimens for NHL, although toxicity is increased.; [Level of evidence: 3iiiA] Recurrences in these patients are common and may not represent the same clonal disease. Immunologic correction through allogeneic SCT is often required to prevent recurrences.
NHL Associated With DNA Repair Defect Syndromes
The incidence of NHL is increased in patients with DNA repair syndromes, including ataxia-telangiectasia, Nijmegen breakage syndrome, and constitutional mismatch repair deficiency. Aggressive mature B-cell NHL accounts for the majority of NHL seen in patients with ataxia-telangiectasia (84%) and Nijmegen breakage syndrome (46%), while T-cell lymphoblastic lymphoma (81%) is observed in patients with constitutional mismatch repair deficiency.
Treatment options for NHL associated with DNA repair defect syndromes
Patients with DNA repair defects are particularly difficult to treat.[7,8] Overall 5-year to 10-year survival rates are poor, at 40% to 60%.[5,9]
Treatment options for NHL associated with DNA repair defect syndromes include the following:
NHL in children with HIV often presents with fever, weight loss, and symptoms related to extranodal disease, such as abdominal pain or CNS symptoms. Most childhood HIV-related NHL is of mature B-cell phenotype but with a spectrum, including primary effusion lymphoma, primary CNS lymphoma, mucosa-associated lymphoid tissue (MALT), Burkitt lymphoma/leukemia, and diffuse large B-cell lymphoma.[10,11]
HIV-associated NHL can be broadly grouped into the following three subcategories:
Highly active antiretroviral therapy has decreased the incidence of NHL in HIV-positive individuals, particularly for primary CNS lymphoma cases.[13,14]
Treatment options for HIV-associated NHL
Treatment options for HIV-associated NHL include the following:
In the era of highly active antiretroviral therapy, children with HIV and NHL are treated with standard chemotherapy regimens for NHL; however, the prevention (using prophylaxis) and early detection of infection is warranted.[1,13,14] Although the number of pediatric patients with HIV-associated NHL is too small to perform meaningful clinical trials, studies of adult patients support the addition of rituximab to standard treatment regimens. Treatment of recurrent disease is based on histology using standard approaches.
Posttransplant Lymphoproliferative Disease (PTLD)
PTLD represents a spectrum of clinically and morphologically heterogeneous lymphoid proliferations. Essentially all PTLDs after HSCT are associated with EBV, but EBV-negative PTLD can be seen after solid organ transplant. While most PTLDs are of B-cell phenotype, approximately 10% are mature (peripheral) T-cell lymphomas. The B-cell stimulation by EBV may result in multiple clones of proliferating B cells, and both polymorphic and monomorphic histologies may be present in a patient, even within the same lesion of PTLD. Thus, histology of a single biopsied site may not be representative of the entire disease process.
The World Health Organization (WHO) has classified PTLD into the following three subtypes:
EBV lymphoproliferative disease posttransplant may manifest as isolated hepatitis, lymphoid interstitial pneumonitis, meningoencephalitis, or an infectious mononucleosis-like syndrome. The definition of PTLD is frequently limited to lymphomatous lesions (low stage or high stage), which are often extranodal (frequently in the allograft). PTLD may less commonly present as a rapidly progressive, high-stage disease that clinically resembles septic shock, and these patients have a poor prognosis; however, the use of rituximab and low-dose chemotherapy may improve outcomes in these patients.[18,19] U.S. transplant and cancer registries show that PTLD accounts for about 3% of all pediatric NHL diagnoses; 65% of PTLDs have diffuse large B-cell lymphoma histology, and 9% of PTLDs have Burkitt histology.
Treatment options for PTLD
Treatment options for PTLD include the following:
First-line therapy for patients with PTLD is to reduce immunosuppressive therapy as much as possible.[25,26] However, this may not be possible because of the increased risk of organ rejection or graft-versus-host disease (GVHD).
Rituximab, an anti-CD20 antibody, has been used in the posttransplant setting. Rituximab as a single agent to treat PTLD after organ transplant has demonstrated efficacy in adult patients, but data are lacking in pediatric patients.
(Refer to the Posttransplantation Lymphoproliferative Disorder [PTLD] section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)
Low-intensity chemotherapy has been effective in patients with EBV-positive, CD20-positive B-lineage PTLD.[19,27] An event-free survival rate of 67% was demonstrated in a Children's Oncology Group study using rituximab plus cyclophosphamide and prednisone in children with PTLD after solid organ transplant in whom immune suppression was reduced.[Level of evidence: 2A] Other studies suggest that modified conventional lymphoma therapy is effective for patients who have PTLD with MYC translocations and Burkitt histology.[23,24][Level of evidence: 3iiDiii] Patients with T-cell or Hodgkin-like PTLD are usually treated with standard lymphoma-specific chemotherapy regimens.[28,29,30,31]
Antirejection therapy is usually decreased or discontinued when chemotherapy is given to avoid excessive toxicity. There are no data to guide the re-initiation of immunosuppressive therapy after chemotherapy treatment. There is little evidence of benefit for chemotherapy after SCT.
Adoptive immunotherapy with either donor lymphocytes or ex vivo –generated EBV-specific cytotoxic T-lymphocytes (EBV-CTLs) has been effective in treating patients with PTLD after blood or bone marrow transplantation.[32,33] To make this approach more broadly applicable, banks of off-the-shelf, third-party, allogeneic EBV-CTLs derived from healthy donors have been developed.[34,35] EBV-CTLs were evaluated in 46 patients with PTLD who had either progressed during rituximab treatment, not fully responded to rituximab treatment, or had a recurrence after a previous response. The following results were observed:
Treatment options under clinical evaluation for PTLD
Low-grade or intermediate-grade mature B-cell lymphomas—such as small lymphocytic lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, mantle cell lymphoma, myeloma, or follicular cell lymphoma—are rarely seen in children. The most recent World Health Organization (WHO) classification has identified pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma as entities separate from their adult counterparts.
The Children's Oncology Group (COG) opened a registry study (COG-ANHL04B1) to learn more about the clinical and pathologic features of these rare types of pediatric non-Hodgkin lymphoma (NHL). This study banks tissue for pathobiology studies and collects limited data on clinical presentation and outcome of therapy.
Pediatric Gray Zone Lymphoma
Gray zone lymphomas represent a hybrid malignancy, with an unclassifiable B-cell lymphoma and classical Hodgkin lymphoma, which may present together in an initial biopsy or sequentially as a relapse.
A retrospective case series study assessed the clinical characteristics and outcomes of six patients with gray zone lymphomas from Austria. The three male and three female patients ranged in age from 15 to 17 years. Two of the six patients had B symptoms and high lactate dehydrogenase (LDH) levels. All patients had mediastinal masses, and five of six patients had positive cervical/supraclavicular lymph nodes. Extranodal involvement of the pleura and lung was common. Initial therapy with B-cell NHL treatments in five patients led to a complete response (CR) in one patient and progressive disease and death in one patient. The other three patients relapsed with primarily classical Hodgkin lymphoma histology and required treatment with salvage therapy. All of these patients survived after high-dose therapies and stem cell transplantations. One patient who initially received Hodgkin lymphoma therapy achieved a CR and survived.
Pediatric-type Follicular Lymphoma
Pediatric-type follicular lymphoma is a disease that genetically and clinically differs from its adult counterpart and is recognized by the WHO classification as a separate entity from follicular lymphoma observed commonly in adults. The genetic hallmark of adult follicular lymphoma is t(14;18)(q32;q21) involving BCL2; however, this translocation must be excluded to make the diagnosis of pediatric-type follicular lymphoma.[1,5,6,7]
Pediatric-type follicular lymphoma predominantly occurs in males, is associated with a high proliferation rate, and is more likely to be localized disease.[5,8,9] In pediatric-type follicular lymphoma, a high-grade component (i.e., grade 3 with high proliferative index such as Ki-67 expression of >30%) resembling diffuse large B-cell lymphoma can frequently be detected at initial diagnosis but does not indicate a more aggressive clinical course in children. Unlike follicular lymphoma in adults, pediatric-type follicular lymphoma does not transform to diffuse large B-cell lymphoma.[1,5,7,9,10] Limited-stage disease is observed with pediatric-type follicular lymphoma, with cervical lymph nodes and tonsils as common sites, but disease has also occurred in extranodal sites such as the testis, kidney, gastrointestinal tract, and parotid gland.[5,6,7,10,11,12]
Genomics of pediatric-type follicular lymphoma
Pediatric-type follicular lymphoma appears to be molecularly distinct from follicular lymphoma that is more commonly observed in adults. The pediatric type lacks BCL2 and IRF4 rearrangements, resulting in IRF4/MUM1 expression. BCL6 and MYC rearrangements are also not present. The TNFSFR14 mutations are common in pediatric-type follicular lymphoma, and they appear to occur with similar frequency in adult follicular lymphoma.[9,14] However, MAP2K1 mutations, which are uncommon in adults, are observed in as many as 43% of pediatric-type follicular lymphoma cases. Other genes (e.g., MAPK1 and RRAS) have been found to be mutated in cases without MAP2K1 mutations, suggesting that the MAP kinase pathway is important in the pathogenesis of pediatric-type follicular lymphoma.[15,16] Mutations in IRF8 and abnormalities in chromosome 1p have also been observed in pediatric-type follicular lymphoma.[14,17,18]
Treatment options for pediatric-type follicular lymphoma
Pediatric-type follicular lymphoma is rare in children, with only case reports and small case series to guide therapy. The outcomes of patients with pediatric-type follicular lymphoma are excellent, with an event-free survival (EFS) rate of about 95%.[5,7,8,9,10,12] Unlike in adult follicular lymphoma, the clinical course in pediatric patients is not dominated by relapses.[5,7,10,11]
Treatment options for pediatric-type follicular lymphoma include the following:
Studies suggest that for children with stage I disease who had a complete resection, a watch-and-wait approach without chemotherapy may be indicated. Patients with higher-stage disease also have a favorable outcome with low-intensity and intermediate-intensity chemotherapy, with an EFS rate of 94% and an overall survival (OS) rate of 100% (2-year median follow-up).[2,5,8,9] Although the number of pediatric patients with pediatric follicular-type lymphoma is too small to perform meaningful clinical trials, studies of adult patients with follicular lymphoma support the addition of rituximab to standard treatment regimens (refer to the Follicular Lymphoma section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information).
For patients with BCL2-rearranged tumors, treatment similar to that of adult patients with follicular lymphoma is administered (refer to the Follicular Lymphoma section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information).
Marginal Zone Lymphoma (Including MALT Lymphoma)
Marginal zone lymphoma is a type of indolent lymphoma that is rare in pediatric patients. Marginal zone lymphoma can present as nodal or extranodal disease and almost always as low-stage (stage I or stage II) disease. It is unclear whether the marginal zone lymphoma that is observed in pediatric patients is clinicopathologically different from the disease that is observed in adults. Most extranodal marginal zone lymphoma in pediatrics presents as MALT lymphoma and may be associated with Helicobacter pylori (gastrointestinal) or Chlamydophila psittaci (conjunctival), previously called Chlamydia psittaci.[19,20]
Treatment options for marginal zone lymphoma (including MALT lymphoma)
Treatment options for marginal zone lymphoma (including MALT lymphoma) include the following:
Most pediatric patients with marginal zone lymphomas require no more than local therapy involving curative surgery and/or radiation therapy.[19,22] Treatment of patients with MALT lymphoma of the gastric mucosa may also include antibiotic therapy, which is considered standard treatment in adults. However, the use of antibiotic therapy in children has not been well studied because there are so few cases.
Evidence (treatment of marginal zone lymphoma):
Although the number of pediatric patients with MALT lymphoma is too small to perform meaningful clinical trials, studies of adult patients support the use of rituximab with or without chemotherapy (refer to the Marginal Zone Lymphoma section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information).
Intralesional interferon-alpha for conjunctival MALT lymphoma has been studied in trials.
Primary Central Nervous System (CNS) Lymphoma
Other types of NHL that are rare in adults and are exceedingly rare in pediatric patients include primary CNS lymphoma. Because of the small numbers of patients, it is difficult to ascertain whether the disease observed in children is the same as the disease observed in adults.
Reports suggest that the outcome of pediatric patients with primary CNS lymphoma (OS rate, 70%–80%) may be superior to that of adults with primary CNS lymphoma.[25,26,27,28]
Most children have diffuse large B-cell lymphoma, although other histologies have been observed.
Treatment options for primary CNS lymphoma
Treatment options for primary CNS lymphoma include the following:
Therapy with high-dose intravenous methotrexate and cytosine arabinoside is the most successful, and intrathecal chemotherapy may be needed only when malignant cells are present in the cerebrospinal fluid.
There are case reports describing the administration of repeated doses of intraventricular rituximab in patients with refractory primary CNS lymphoma, with excellent results reported.[30,31] This apparently good outcome needs to be confirmed, and similar results have not been observed in adults. It is generally believed that rituximab does not cross the blood-brain barrier.
Among patients who have a partial response to induction therapy, and particularly those who are not eligible for transplant, reduced-dose whole-brain radiation therapy with a boost to residual disease may be a viable treatment approach that merits further investigation.[32,33]
(Refer to the PDQ summary on Primary CNS Lymphoma Treatment for more information about treatment options for non–AIDS-related primary CNS lymphoma.)
Peripheral T-cell Lymphoma
Peripheral T-cell lymphoma, excluding anaplastic large cell lymphoma, is rare in children.
Mature T-cell/natural killer (NK)–cell lymphoma or peripheral T-cell lymphoma has a postthymic phenotype (e.g., terminal deoxynucleotidyl transferase negative), usually expresses CD4 or CD8, and has rearrangement of T-cell receptor genes, either alpha-beta and/or gamma-delta chains. The most common phenotype observed in children is peripheral T-cell lymphoma–not otherwise specified, although angioimmunoblastic lymphoma, enteropathy-associated lymphoma (associated with celiac disease), subcutaneous panniculitis-like lymphoma, angiocentric lymphoma, and extranodal NK/T-cell peripheral T-cell lymphoma have been reported.[34,35,36,37,38]
Extranodal NK/T-cell lymphoma is a rare subtype of NHL, constitutes between 0.2% and 1.6% of newly diagnosed cases of NHL in children and adolescents, and is closely associated with the Epstein-Barr virus (EBV). The incidence varies by region; the incidence is between 3% and 10% in Asian countries and 1% in western countries. The common primary tumor sites are the nasal cavity and paranasal sinuses. A standard treatment for pediatric patients has not been established. A series of 34 patients were treated with chemotherapy with or without asparaginase. At a median follow-up of 54 months, patients with lower-stage (I/II) disease had 5-year EFS and OS rates of 66.2% and 94.7%, respectively, compared with 26.0% and 42.3% for patients with stage III/IV disease. For all patients, there was no statistically significant difference in outcomes between patients who received asparaginase-containing regimens and those who did not. All patients with stage I/II disease received radiation therapy, whereas only 4 of 13 patients with higher-stage disease received radiation therapy. The 5-year EFS rate was 66.7% for stage III/IV patients who received hematopoietic stem cell transplantation (HSCT) and 11.1% for patients who did not receive HSCT (P = .054).[Level of evidence: 3iii]
Although very rare, gamma-delta hepatosplenic T-cell lymphoma may be seen in children. This tumor has also been associated with children and adolescents who have Crohn disease and have been treated with immunosuppressive therapy; this lymphoma has been fatal in all cases.
Treatment options for peripheral T-cell lymphoma
Optimal therapy for peripheral T-cell lymphoma is unclear for both pediatric and adult patients.
Treatment options for peripheral T-cell lymphoma include the following:
There have been four retrospective analyses of treatment and outcome for pediatric patients with peripheral T-cell lymphoma.
Evidence (treatment of peripheral T-cell lymphoma):
Cutaneous T-cell Lymphoma/Mycosis Fungoides
Primary cutaneous lymphomas are very rare in pediatric patients (1 case per 1 million person-years), but the incidence increases in adolescents and young adults. All histologies of NHL have been observed to involve the skin. More than 80% of cutaneous lymphomas are the T-cell or NK-cell phenotype.
Subcutaneous panniculitic T-cell lymphomas are very rare lymphomas with panniculitis-like infiltration of subcutaneous tissue by cytotoxic T-cells.[46,47,48] Subcutaneous panniculitic T-cell lymphoma can be observed with malignant T cells, expressing alpha-beta chain T-cell receptor or gamma-delta T-cell receptor rearrangements.
In adults, the gamma-delta subtype of subcutaneous panniculitic T-cell lymphoma is associated with a more aggressive course and a worse prognosis than is the alpha-beta subtype of subcutaneous panniculitic T-cell lymphoma. Morbidity and mortality are frequently related to the development of hemophagocytic syndrome, which was reported in one series in adults to occur in 17% of patients with alpha-beta subcutaneous panniculitic T-cell lymphoma and in 45% of patients with gamma-delta subcutaneous panniculitic T-cell lymphoma. The 5-year OS rate is 82% for patients with alpha-beta subcutaneous panniculitic T-cell lymphoma and 11% for patients with gamma-delta subcutaneous panniculitic T-cell lymphoma. Subcutaneous panniculitic T-cell lymphoma is heterogeneous in the pediatric age group and does not necessarily follow the course that is observed in adults. In a series of 11 pediatric patients with subcutaneous panniculitis-like T-cell lymphoma, most presented with multifocal disease (often on the trunk) and systemic symptoms (fever), and there was a frequent association with hemophagocytic syndrome.
The diagnosis of primary cutaneous anaplastic large cell lymphoma can be difficult to distinguish pathologically from more benign diseases such as lymphomatoid papulosis. Primary cutaneous lymphomas are now thought to represent a spectrum of disorders, distinguished by clinical presentation.
Mycosis fungoides is rarely reported in children and adolescents,[52,53,54] accounting for about 0.5% to 7% of all cases. In a systematic review of 571 children and adolescents with mycosis fungoides, the mean age of diagnosis was 12.2 years, and the mean age at onset was 8.6 years. The female-to-male ratio was 1:1.6 (similar to adults). The most common subtype was the hypopigmented form, followed by classic mycosis fungoides. Most patients presented with stage 1 disease (91.6%), which is in contrast to the general population, where only 65.8% to 82.2% of patients present with early-stage disease. The mycosis fungoides lesions were predominantly CD4 positive (49.5%) and CD8 positive (39.5%); however, patients with CD8-positive lesions were significantly younger than the pediatric patients with CD4-positive predominant lesions (7.9 years vs. 9.8 years at onset). The most frequently used treatment was narrowband ultraviolet B (UVB) phototherapy. Most patients were alive with disease (66.3%), 29.8% of patients were in complete remission, and 3.9% of patients had died by the time of the last follow-up. Factors associated with worse overall 10-year survival were delay in establishing the correct diagnosis, granulomatous slack skin, granulomatous mycosis fungoides, history of organ transplant, and stage 2 disease at the time of diagnosis.[Level of evidence: 3iiiDiv] (Refer to the PDQ summary on Mycosis Fungoides [Including Sézary Syndrome] Treatment for information about the treatment of adult patients.)
Treatment options for cutaneous T-cell lymphoma/mycosis fungoides
Because of the rarity of cutaneous T-cell lymphoma, no standard treatments have been established. Management and treatment of patients with cutaneous T-cell lymphoma should be individualized and, in some cases, watchful waiting may be appropriate. Treatment may only be necessary if hemophagocytic syndrome develops.
The best treatment for patients who have T-cell lymphomas with primarily pannicular involvement is not known. Treatment options include high-dose steroids, bexarotene, denileukin diftitox, multiagent chemotherapy, and HSCT.[48,56,57,58,59,60,61]
An oral retinoid (bexarotene) has been reported to be active against subcutaneous panniculitis-like T-cell lymphomas in a series of 15 patients from three institutions. In a series of 11 pediatric patients, aggressive polychemotherapy was used in all patients. Nine of 11 patients sustained clinical remission, with a median follow-up of 3.5 years. In general, however, the optimal therapy for non–anaplastic large cell lymphoma cutaneous T-cell lymphoma in childhood is unclear.
Primary cutaneous anaplastic large cell lymphoma usually does not express ALK and may be treated successfully with surgical resection and/or local radiation therapy without systemic chemotherapy. There are reports of surgery alone also being curative for patients with ALK-positive cutaneous anaplastic large cell lymphoma, but extensive staging and vigilant follow-up is required.[63,64]
Mycosis fungoides occurring in pediatric patients may respond to various therapies, including topical steroids, retinoids, radiation therapy, or phototherapy (e.g., narrowband UVB treatment), but remission may not be durable.[65,66,67,68]
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Aggressive Mature B-cell Non-Hodgkin Lymphoma (NHL)
Added text about the ANHL1931 trial as a treatment option under clinical evaluation for primary mediastinal B-cell lymphoma.
The Standard Treatment Options for Lymphoblastic Lymphoma subsection was extensively revised.
Anaplastic Large Cell Lymphoma
Added ceritinib as a treatment option for recurrent or refractory anaplastic large cell lymphoma (cited Fischer et al. as reference 35).
Rare NHL Occurring in Children
Revised subsection title from Cutaneous T-cell Lymphoma to Cutaneous T-cell Lymphoma/Mycosis Fungoides.
Revised text to state that mycosis fungoides is rarely reported in children and adolescents, accounting for about 0.5% to 7% of all cases. Also added text about the results of a systematic review of 571 children and adolescents with mycosis fungoides, including incidence, clinical presentation, immunophenotypes, treatments, and outcomes (cited Jung et al. as reference 55 and level of evidence 3iiiDiv).
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood non-Hodgkin lymphoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Non-Hodgkin Lymphoma Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Non-Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lymphoma/hp/child-nhl-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389181]
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Last Revised: 2022-04-01
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