Childhood Non-Hodgkin Lymphoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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Childhood Non-Hodgkin Lymphoma Treatment

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood non-Hodgkin lymphoma. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.

Information about the following is included in this summary:

  • Incidence.
  • Cellular classification.
  • Clinical presentation.
  • Stage information.
  • Treatment options.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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 and Adult Treatment Editorial Boards use a formal evidence ranking system in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less technical language, and in Spanish.

General Information

The National Cancer Institute (NCI) provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Cancer in children and adolescents is rare. 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 primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive 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.

Guidelines for pediatric cancer centers and their role in the treatment of children with cancer have been outlined by the American Academy of Pediatrics.[1] At these pediatric cancer centers, clinical trials are available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up 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.

Lymphoma (Hodgkin lymphoma and non-Hodgkin lymphoma [NHL]) is the third most common childhood malignancy, and NHL accounts for approximately 7% of cancers in children younger than 20 years.[2,3] In the United States, about 800 new cases of NHL are diagnosed each year. The incidence is approximately 10 cases per 1,000,000 people per year. Although there is no sharp age peak, NHL occurs most commonly in the second decade of life, and occurs less frequently in children younger than 3 years. NHL in infants is rare (1% in Berlin-Frankfurt-Munster trials from 1986 to 2002). In this retrospective review, the outcome for infants was inferior compared with older patients with NHL.[4][Level of evidence: 3iiA] The incidence of NHL is increasing overall, and there is a slight increase in the incidence for those aged 15 to 19 years; however, the incidence of NHL in children younger than 15 years has remained constant over the past several decades.[2] The incidence of NHL is higher in Caucasians than in African Americans, and NHL is more common in males than in females.[2,5] Immunodeficiency, both congenital and acquired (human immunodeficiency virus infection or posttransplant immunodeficiency), increases the risk of NHL. Epstein-Barr virus is associated with most cases of NHL seen in the immunodeficient population.[2,3]

With current treatments, more than 80% of children and adolescents with NHL will survive at least 5 years, though outcome is variable depending on a number of factors, including clinical stage and histology.[5] Patients with localized disease (i.e., single extra-abdominal/extrathoracic tumor or totally resected intra-abdominal tumor) have an excellent prognosis (a 5-year survival rate of approximately 90%), regardless of histology.[6,7,8,9,10] Patients with NHL arising in bone have an excellent prognosis regardless of histology.[11,12] Testicular involvement does not affect prognosis.[7,13] Unlike adults, children and adolescents with nonlymphoblastic NHL involving the mediastinum have an inferior outcome, as compared with other sites of disease.[5,8,14] Patients with leukemic involvement (>25% blasts in marrow) or central nervous system (CNS) involvement at diagnosis require intensive therapy.[7,15,16] Although these intensive therapies have improved the outcome for patients with disseminated or advanced-stage disease, patients who present with CNS disease have the worst outcome.[7,15,16]

Information about ongoing clinical trials is available from the NCI Web site.

References:

1. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.
2. Percy CL, Smith MA, Linet M, et al.: Lymphomas and reticuloendothelial neoplasms. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649., pp 35-50. Also available online. Last accessed July 16, 2009.
3. Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996.
4. Mann G, Attarbaschi A, Burkhardt B, et al.: Clinical characteristics and treatment outcome of infants with non-Hodgkin lymphoma. Br J Haematol 139 (3): 443-9, 2007.
5. Burkhardt B, Zimmermann M, Oschlies I, et al.: The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol 131 (1): 39-49, 2005.
6. Link MP, Shuster JJ, Donaldson SS, et al.: Treatment of children and young adults with early-stage non-Hodgkin's lymphoma. N Engl J Med 337 (18): 1259-66, 1997.
7. Reiter A, Schrappe M, Ludwig WD, et al.: Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report. Blood 95 (2): 416-21, 2000.
8. Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005.
9. Gerrard M, Cairo MS, Weston C, et al.: Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Br J Haematol 141 (6): 840-7, 2008.
10. Seidemann K, Tiemann M, Schrappe M, et al.: Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 97 (12): 3699-706, 2001.
11. Lones MA, Perkins SL, Sposto R, et al.: Non-Hodgkin's lymphoma arising in bone in children and adolescents is associated with an excellent outcome: a Children's Cancer Group report. J Clin Oncol 20 (9): 2293-301, 2002.
12. Zhao XF, Young KH, Frank D, et al.: Pediatric primary bone lymphoma-diffuse large B-cell lymphoma: morphologic and immunohistochemical characteristics of 10 cases. Am J Clin Pathol 127 (1): 47-54, 2007.
13. Dalle JH, Mechinaud F, Michon J, et al.: Testicular disease in childhood B-cell non-Hodgkin's lymphoma: the French Society of Pediatric Oncology experience. J Clin Oncol 19 (9): 2397-403, 2001.
14. Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007.
15. Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007.
16. Salzburg J, Burkhardt B, Zimmermann M, et al.: Prevalence, clinical pattern, and outcome of CNS involvement in childhood and adolescent non-Hodgkin's lymphoma differ by non-Hodgkin's lymphoma subtype: a Berlin-Frankfurt-Munster Group Report. J Clin Oncol 25 (25): 3915-22, 2007.

Cellular Classification

Cellular Classification and Clinical Presentation

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Editorial Boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

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.[1,2,3] The World Health Organization (WHO) has classified NHL on the basis of the following: (1) phenotype (i.e., B-lineage and T-lineage or natural killer [NK] cell lineage); and (2) differentiation (i.e., precursor versus mature).[1] Classification of NHL in childhood and adolescence has historically been based on clinical behavior and response to treatment. A study by the Children's Cancer Group demonstrated that the outcome for lymphoblastic NHL was superior with longer leukemia-like therapy consisting of induction, consolidation, and maintenance, while nonlymphoblastic NHL (Burkitt and large cell) had superior outcome with short, intensive, pulsed therapy.[4] In general, these treatment principles still apply.

On the basis of clinical response to treatment, NHL of childhood and adolescence currently falls into three therapeutically relevant categories: (1) mature B-cell NHL (Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma [DLBCL]); (2) lymphoblastic lymphoma (primarily precursor T-cell lymphoma and, less frequently, precursor B-cell lymphoma); and (3) anaplastic large cell lymphoma (mature T-cell or null-cell lymphomas). NHL associated with immunodeficiency generally has a mature B-cell phenotype and is more often of large cell than Burkitt histology.[5] Posttransplant lymphoproliferative diseases (PTLDs) are classified according to standard NHL nomenclature as (1) early lesions, (2) polymorphic, and (3) monomorphic.[1]

Other types of lymphomas are more commonly seen in adults and occur rarely in children. (Refer to the PDQ summaries on the treatment of Adult Non-Hodgkin Lymphoma, Primary CNS Lymphoma, and Mycosis Fungoides and the Sézary Syndrome for more information.)

Each type of childhood NHL is associated with distinctive molecular biological characteristics, which are outlined in the following table. The Revised European-American Lymphoma (REAL) classification and the WHO classification [1] are the most current NHL classifications utilized and are shown below. [2] The Working Formulation is also listed for reference. The WHO Classification applies the principles of the REAL classification and focuses on the specific type of lymphoma for therapy purposes. The remainder of the categories, for the most part, do not pertain to pediatric NHL and are not shown.

Table 1. Major Histopathological Categories of Non-Hodgkin Lymphoma in Children and Adolescentsa

CNS = central nervous system; ML = malignant lymphoma.
a Adapted from Percy et al.[2]
Category (WHO Classification/ Updated REAL) Category (Working Formulation) Immuno-phenotype Clinical Presentation Chromosome Translocation Genes Affected
Burkitt and Burkitt-like lymphomas ML small noncleaved cell Mature B cell Intra-abdominal (sporadic), head and neck (non-jaw, sporadic), jaw (endemic) t(8;14)(q24 q32), t(2;8)(p11;q24), t(8;22)(q24; q11) C-MYC, IGH, IGK, IGL
Diffuse large B-cell lymphoma ML large cell Mature B cell; maybe CD30+ Nodal, abdomen, bone, primary CNS, mediastinal No consistent cytogenetic abnormality identified  
Lymphoblastic lymphoma, precursor T-cell/leukemia, or precursor B-cell lymphoma Lymphoblastic convoluted and non-convoluted Pre-T cell Mediastinal, bone marrow MTS1/p16ink4a Deletion TAL1 t(1;14)(p34; q11), t(11;14)(p13;q11) TAL1, TCRAO, RHOMB1, HOX11
Pre-B cell Skin, bone
Anaplastic large cell lymphoma, systemic ML immunoblastic or ML large CD30+ (Ki-1+) Variable, but systemic symptoms often prominent t(2;5)(p23; q35) ALK, NPM
T cell or null cell
Anaplastic large cell lymphoma, cutaneous   CD30+ (Ki-usually) Skin only; single or multiple lesions Lacks t(2;5)  
T cell

Burkitt and Burkitt-like lymphoma/leukemia

Burkitt and Burkitt-like lymphoma/leukemia accounts for about 50% of childhood NHL and exhibits consistent, aggressive clinical behavior.[1,2,3,6] The two most common primary sites of disease are the abdomen and the head and neck region.[3] Other sites of involvement include testes, bone, peripheral lymph nodes, skin, bone marrow, and central nervous system (CNS). Although 85% or more of Burkitt lymphoma is associated with the Epstein Barr virus (EBV) in endemic Africa, approximately 15% of cases in Europe or the United States will have EBV detectable in the tumor tissue.[7]

The malignant cells show a mature B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase (TdT). These malignant cells usually express surface immunoglobulin, most bearing surface immunoglobulin M with either kappa or lambda light chains. A variety of additional B-cell markers (e.g., CD20, CD22) are usually present, and almost all childhood Burkitt/Burkitt-like lymphoma/leukemia express CALLA (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 c-myc gene to immunoglobulin locus regulatory elements, resulting in the inappropriate expression of c-myc, the gene involved in cellular proliferation. Pediatric Burkitt lymphoma patients whose tumors also contain cytogenetic abnormalities of 7q, 13q, or 22q have an inferior outcome on current chemotherapy protocols.[8,9][Level of evidence: 3iiiA]

The distinction between Burkitt and Burkitt-like lymphoma/leukemia is controversial. Burkitt lymphoma consists of uniform, small, noncleaved cells, whereas Burkitt-like lymphoma is a highly disputed diagnosis among pathologists owing to features that are consistent with DLBCL.[1] Cytogenetic evidence of c-myc rearrangement is the gold standard for diagnosis of Burkitt lymphoma. For cases in which cytogenetic analysis is not available, the WHO has recommended that the Burkitt-like diagnosis be reserved for lymphoma resembling Burkitt lymphoma or with more pleomorphism, large cells, and a proliferation fraction (i.e., Ki-67[+] of at least 99%).[1] Studies have demonstrated that the vast majority of Burkitt-like or "atypical Burkitt" lymphomas have a gene expression signature similar to Burkitt lymphoma.[10][Level of evidence: 3iiiA] Additionally, as many as 30% of pediatric DLBCL cases will have a gene signature similar to Burkitt lymphoma.[10,11,12][Level of evidence: 3iiiA] Despite the histologic differences, Burkitt and Burkitt-like lymphoma/leukemia are clinically very aggressive and are treated with very aggressive regimens.[13,14,15,16]

Diffuse large B-cell lymphoma

DLBCL is a mature B-cell neoplasm that represents 10% to 20% of pediatric NHL. DLBCL occurs more frequently during the second decade of life than during the first decade.[2,6,17] The WHO classification system does not recommend morphologic subclassification based on morphologic variants (e.g., immunoblastic, centroblastic) of DLBCL.[1] Pediatric DLBCL may present clinically similar to Burkitt or Burkitt-like lymphoma, though it is more often localized and less often involves the bone marrow or CNS.[6,18] As many as 30% of patients younger than 14 years with DLBCL will have a gene signature similar to Burkitt lymphoma.[10][Level of evidence: 3iiiA]

Excluding primary mediastinal B-cell lymphoma, DLBCL in children and adolescents differs biologically from DLBCL in adults. The vast majority of pediatric DLBCL cases have a germinal center B-cell phenotype, as assessed by immunohistochemical analysis of selected proteins found in normal germinal center B cells.[17,19][Level of evidence: 3iiiDi] Unlike adult DLBCL of the germinal center B-cell type, in which the t(14;18) translocation involving the immunoglobulin heavy-chain gene and the BCL2 gene is commonly observed, pediatric DLBCL rarely demonstrates the t(14;18) translocation.[17] Outcomes for children with DLBCL are more favorable than those observed in adults, with overall 5-year event-free survival rates of approximately 90% in children.[14,15,16]

About 20% of pediatric DLBCL presents as primary mediastinal disease (primary mediastinal B-cell lymphoma [PMBCL]). This presentation is more common in older children and adolescents and is associated with an inferior outcome compared with other pediatric DLBCL.[6,14,15,20,21] PMBCL is associated with distinctive chromosomal aberrations (gains in chromosome 9p and 2p in regions that involve JAK2 and c-rel, respectively) [21] and commonly shows inactivation of SOCS1 by either mutation or gene deletion.[22,23] PMBCL also has a distinctive gene expression profile in comparison with other DLBCL, suggesting a close relationship of PMBCL with Hodgkin lymphoma.[24,25]

Lymphoblastic lymphoma

Lymphoblastic lymphoma makes up approximately 20% to 30% of childhood NHL.[2,3,6] Lymphoblastic lymphomas are usually positive for TdT, with more than 75% having a T-cell immunophenotype and the remainder having a precursor B-cell phenotype.[1,3,26] Chromosomal abnormalities are not well characterized in patients with lymphoblastic lymphoma. However, one study demonstrated that loss of heterozygosity on chromosome 6q in T-cell lymphoblastic lymphoma patients was associated with an increased risk of relapse.[27][Level of evidence: 3iiDi]

As many as 75% of patients with 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 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, CNS, abdominal organs (but rarely bowel), and occasionally other sites such as lymphoid tissue of Waldeyer ring and testes. Abdominal involvement is rare compared with Burkitt lymphoma. Localized lymphoblastic lymphoma may occur in lymph nodes, bone, and subcutaneous tissue. Lymphoblastic lymphoma within the mediastinum is not considered localized disease.

Involvement of the bone marrow may lead to confusion as to 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 leukemia, and those with fewer than 25% marrow blasts are considered to have lymphoma. It is not yet clear whether these arbitrary definitions are biologically distinct or relevant for treatment design.

Anaplastic large cell lymphoma

Anaplastic large cell lymphoma (ALCL) accounts for approximately 10% of childhood NHL.[6] While the predominant immunophenotype of ALCL is mature T-cell, null-cell disease (i.e., no T-cell, B-cell, or NK-cell surface antigen expression) does occur. The WHO classification system classifies ALCL as a peripheral T-cell lymphoma (PTCL).[1] Many view ALK+ ALCL differently than other PTCL because prognosis tends to be superior to other forms of PTCL.[28] More than 90% of ALCL cases are CD30-positive and have the translocation t(2;5)(p23;q35) leading to the expression of the fusion protein NPM/ALK, though variant ALK translocations have been reported.[29] Clinically, ALCL has a broad range of presentations, including 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 CNS and bone marrow is uncommon. ALCL 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 ALCL may present with signs and symptoms consistent with hemophagocytic lymphohistiocytosis but have mediastinal or other adenopathy that, when biopsied, is diagnostic of ALCL.[30] There is a subgroup of ALCL with leukemic peripheral blood involvement. These patients usually exhibit significant respiratory distress with diffuse lung infiltrates or pleural effusions and have hepatosplenomegaly. Most of these cases have an aberrant T-cell immunophenotype with frequent expression of myeloid antigens. Patients in this ALCL subgroup may require more aggressive therapy.[31,32] In a retrospective subset analysis, there was evidence that submicroscopic bone marrow and peripheral blood involvement, detected by reverse transcriptase-polymerase chain reaction (RT-PCR) from NPM-ALK, was found in approximately 50% of patients and correlated with clinical stage;[33] and marrow involvement detected by PCR was associated with a 50% cumulative incidence of relapse.

Lymphoproliferative disease associated with immunodeficiency in children

The incidence of lymphoproliferative disease or lymphoma is 100-fold higher in immunocompromised children than in the general population. The cause of such immune deficiencies may be a genetically inherited defect, secondary to human immunodeficiency virus (HIV) infection, or iatrogenic following transplantation (solid organ transplantation or allogeneic hematopoietic stem cell transplantation [HSCT]). EBV is associated with most of these tumors, but some tumors are not associated with any infectious agent.

NHL associated with HIV is usually aggressive, with most cases occurring in extralymphatic sites.[34] HIV-associated NHL can be broadly grouped into three subcategories: systemic (nodal and extranodal), primary CNS lymphoma (PCNSL), and body cavity–based lymphoma, also referred to as primary effusion lymphoma (PEL). Approximately 80% of all NHL in HIV patients is considered to be systemic.[34] PEL, a unique lymphomatous effusion associated with the human herpesvirus-8 (HHV8) gene or Kaposi sarcoma herpesvirus, is primarily observed in adults infected with HIV but has been reported in HIV-infected children.[35] Highly active antiretroviral therapy has decreased the incidence of NHL in HIV-positive individuals, particularly for PCNSL cases.[36] Most childhood HIV-related NHL is of mature B-cell phenotype but with a spectrum including PEL, PCSNL, mucosa-associated lymphoid tissue (MALT),[37] Burkitt lymphoma,[38] and diffuse large cell lymphoma. NHL in children with HIV often presents with fever, weight loss, and symptoms related to extranodal disease, such as abdominal pain or CNS symptoms.[34]

NHL observed in primary immunodeficiency usually shows a mature B-cell phenotype and large cell histology.[5] Mature T-cell and anaplastic large cell lymphoma have been observed.[5] Children with primary immunodeficiency and NHL are more likely to have disseminated disease and present with symptoms related to extranodal disease, particularly the gastrointestinal tract and CNS.[5]

PTLD represents a spectrum of clinically and morphologically heterogeneous lymphoid proliferations. Essentially all PTLD following HSCT is associated with EBV, but EBV-negative PTLD can be seen following solid organ transplant.[39] The WHO has classified PTLD into three subtypes: early lesions, polymorphic PTLD, and monomorphic PTLD.[40] Early lesions show germinal center expansion but tissue architecture remains normal. Presence of infiltrating T cells, disruption of nodal architecture, and necrosis distinguish polymorphic PTLD from early lesions. Histologies observed in the monomorphic subtype are similar to those observed in NHL, with DLBCL being the most common histology, followed by Burkitt lymphoma, with myeloma or plasmacytoma occurring rarely. The B-cell stimulation by EBV may result in multiple clones of proliferating B cells, and both polymorphous and monomorphous histologies may be present in a patient, even within the same lesion of PTLD.[41] Thus, histology of a single biopsied site may not be representative of the entire disease process. Not all PTLD is B-cell phenotype.[40] 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 (localized or diffuse), which are often extranodal (frequently in the allograft).[39] Although less common, PTLD may present as a rapidly progressive, disseminated disease that clinically resembles septic shock, which almost always results in death despite therapy.[42]

Rare non-Hodgkin lymphoma occurring in children

Mature B-cell lymphomas such as small lymphocytic, MALT, mantle cell lymphoma, myeloma, or follicular cell lymphoma are rarely seen in children. It is unclear whether these histologies observed in children are the same diseases as those seen in adults.[43,44] For example, follicular lymphoma observed in children express bcl-2 only in a small number of cases.[44] However, other diseases appear to reflect the disease observed in adult patients. For example, MALT lymphomas observed in pediatric patients usually present as localized disease and are associated with H. pylori and require no more than local therapy of surgery and/or radiation therapy to cure.[43]

Other types of NHL may be rare in adults and are exceedingly rare in pediatric patients, such as primary cutaneous lymphoma and PCNSL. Due to small numbers, it is difficult to ascertain if the disease observed in children is the same as in adults and, therefore, it is difficult to determine optimal therapy. Reports suggest that the outcome of pediatric patients with PCNSL may be superior to that of adults with PCNSL. These reports suggest that long-term survival can be achieved without cranial irradiation.[45,46] One report showed that most of the children had DLBCL or ALCL. Results of this study showed that therapy with high-dose intravenous methotrexate and cytosine arabinoside was most successful and that intrathecal chemotherapy may be needed only when malignant cells are present in the cerebral spinal fluid.[46] There is a case report of repeated doses of rituxumab, both intravenous and intraventricular, being administered to a 14-year-old boy with refractory primary CNS lymphoma, with an excellent result.[47] This apparently good outcome needs to be confirmed especially since similar results have not been observed in adults.

Peripheral T-cell lymphoma (PTCL), excluding anaplastic large cell lymphoma, is very rare in children. Mature T-cell/NK-cell lymphoma or PTCL has a postthymic phenotype (e.g., TdT negative), usually expresses CD4 or CD8, and has rearrangement of T-cell receptor (TCR) genes, either alpha/beta and/or gamma/delta chains. The most common phenotype observed in children is PTCL-unspecified, although angioimmunoblastic lymphoma (AITL), enteropathy-associated lymphoma (EATL) (associated with celiac disease), subcutaneous panniculitis-like lymphoma, angiocentriclymphoma, and extranodal NK/T-cell PTCL have been reported.[48][Level of evidence: 3iA ][49][Level of evidence: 3iiiA] Though very rare, hepatosplenic T-cell lymphoma is associated with children and adolescents who have Crohn disease and has been fatal in all cases.[50] Optimal therapy for PTCL is unclear, even for adult patients. There have been two retrospective analyses of treatment and outcome for pediatric patients with PTCL. The United Kingdom Children's Cancer Study Group (UKCCSG) reported 25 children younger than 20 years with PTCL, with an approximate 50% 5-year survival rate.[48][Level of evidence: 3iA] The UKCCSG also observed that the use of ALL-like therapy, instead of NHL therapy, produced a superior outcome. The Children's Oncology Group (COG) reported 20 patients older than 8 years treated on Pediatric Oncology Group NHL trials.[49][Level of evidence: 3iiiA] Eight of ten patients with localized disease achieved long-term disease-free survival compared to only four of ten patients with disseminated disease.

In an attempt to learn more about the clinical and pathologic features of these types of NHL seen rarely in children, the COG has opened a registry study. This study banks tissue for pathobiology studies and collects limited data on clinical presentation and outcome to therapy.

References:

1. Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3.
2. Percy CL, Smith MA, Linet M, et al.: Lymphomas and reticuloendothelial neoplasms. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649., pp 35-50. Also available online. Last accessed July 16, 2009.
3. Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996.
4. Anderson JR, Jenkin RD, Wilson JF, et al.: Long-term follow-up of patients treated with COMP or LSA2L2 therapy for childhood non-Hodgkin's lymphoma: a report of CCG-551 from the Childrens Cancer Group. J Clin Oncol 11 (6): 1024-32, 1993.
5. Seidemann K, Tiemann M, Henze G, et al.: Therapy for non-Hodgkin lymphoma in children with primary immunodeficiency: analysis of 19 patients from the BFM trials. Med Pediatr Oncol 33 (6): 536-44, 1999.
6. Burkhardt B, Zimmermann M, Oschlies I, et al.: The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol 131 (1): 39-49, 2005.
7. Gutiérrez MI, Bhatia K, Barriga F, et al.: Molecular epidemiology of Burkitt's lymphoma from South America: differences in breakpoint location and Epstein-Barr virus association from tumors in other world regions. Blood 79 (12): 3261-6, 1992.
8. Onciu M, Schlette E, Zhou Y, et al.: Secondary chromosomal abnormalities predict outcome in pediatric and adult high-stage Burkitt lymphoma. Cancer 107 (5): 1084-92, 2006.
9. Poirel HA, Cairo MS, Heerema NA, et al.: Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Leukemia 23 (2): 323-31, 2009.
10. Klapper W, Szczepanowski M, Burkhardt B, et al.: Molecular profiling of pediatric mature B-cell lymphoma treated in population-based prospective clinical trials. Blood 112 (4): 1374-81, 2008.
11. Cairo MS, Raetz E, Lim MS, et al.: Childhood and adolescent non-Hodgkin lymphoma: new insights in biology and critical challenges for the future. Pediatr Blood Cancer 45 (6): 753-69, 2005.
12. Dave SS, Fu K, Wright GW, et al.: Molecular diagnosis of Burkitt's lymphoma. N Engl J Med 354 (23): 2431-42, 2006.
13. Sevilla DW, Gong JZ, Goodman BK, et al.: Clinicopathologic findings in high-grade B-cell lymphomas with typical Burkitt morphologic features but lacking the MYC translocation. Am J Clin Pathol 128 (6): 981-91, 2007.
14. Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005.
15. Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007.
16. Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007.
17. Oschlies I, Klapper W, Zimmermann M, et al.: Diffuse large B-cell lymphoma in pediatric patients belongs predominantly to the germinal-center type B-cell lymphomas: a clinicopathologic analysis of cases included in the German BFM (Berlin-Frankfurt-Munster) Multicenter Trial. Blood 107 (10): 4047-52, 2006.
18. Lones MA, Perkins SL, Sposto R, et al.: Large-cell lymphoma arising in the mediastinum in children and adolescents is associated with an excellent outcome: a Children's Cancer Group report. J Clin Oncol 18 (22): 3845-53, 2000.
19. Miles RR, Raphael M, McCarthy K, et al.: Pediatric diffuse large B-cell lymphoma demonstrates a high proliferation index, frequent c-Myc protein expression, and a high incidence of germinal center subtype: Report of the French-American-British (FAB) international study group. Pediatr Blood Cancer 51 (3): 369-74, 2008.
20. Seidemann K, Tiemann M, Lauterbach I, et al.: Primary mediastinal large B-cell lymphoma with sclerosis in pediatric and adolescent patients: treatment and results from three therapeutic studies of the Berlin-Frankfurt-Münster Group. J Clin Oncol 21 (9): 1782-9, 2003.
21. Bea S, Zettl A, Wright G, et al.: Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood 106 (9): 3183-90, 2005.
22. Melzner I, Bucur AJ, Brüderlein S, et al.: Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma line. Blood 105 (6): 2535-42, 2005.
23. Mestre C, Rubio-Moscardo F, Rosenwald A, et al.: Homozygous deletion of SOCS1 in primary mediastinal B-cell lymphoma detected by CGH to BAC microarrays. Leukemia 19 (6): 1082-4, 2005.
24. Rosenwald A, Wright G, Leroy K, et al.: Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med 198 (6): 851-62, 2003.
25. Savage KJ, Monti S, Kutok JL, et al.: The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 102 (12): 3871-9, 2003.
26. Neth O, Seidemann K, Jansen P, et al.: Precursor B-cell lymphoblastic lymphoma in childhood and adolescence: clinical features, treatment, and results in trials NHL-BFM 86 and 90. Med Pediatr Oncol 35 (1): 20-7, 2000.
27. Burkhardt B, Moericke A, Klapper W, et al.: Pediatric precursor T lymphoblastic leukemia and lymphoblastic lymphoma: Differences in the common regions with loss of heterozygosity at chromosome 6q and their prognostic impact. Leuk Lymphoma 49 (3): 451-61, 2008.
28. Savage KJ, Harris NL, Vose JM, et al.: ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 111 (12): 5496-504, 2008.
29. Duyster J, Bai RY, Morris SW: Translocations involving anaplastic lymphoma kinase (ALK). Oncogene 20 (40): 5623-37, 2001.
30. Sevilla DW, Choi JK, Gong JZ: Mediastinal adenopathy, lung infiltrates, and hemophagocytosis: unusual manifestation of pediatric anaplastic large cell lymphoma: report of two cases. Am J Clin Pathol 127 (3): 458-64, 2007.
31. Onciu M, Behm FG, Raimondi SC, et al.: ALK-positive anaplastic large cell lymphoma with leukemic peripheral blood involvement is a clinicopathologic entity with an unfavorable prognosis. Report of three cases and review of the literature. Am J Clin Pathol 120 (4): 617-25, 2003.
32. Grewal JS, Smith LB, Winegarden JD 3rd, et al.: Highly aggressive ALK-positive anaplastic large cell lymphoma with a leukemic phase and multi-organ involvement: a report of three cases and a review of the literature. Ann Hematol 86 (7): 499-508, 2007.
33. Damm-Welk C, Busch K, Burkhardt B, et al.: Prognostic significance of circulating tumor cells in bone marrow or peripheral blood as detected by qualitative and quantitative PCR in pediatric NPM-ALK-positive anaplastic large-cell lymphoma. Blood 110 (2): 670-7, 2007.
34. McClain KL, Joshi VV, Murphy SB: Cancers in children with HIV infection. Hematol Oncol Clin North Am 10 (5): 1189-201, 1996.
35. Jaffe ES: Primary body cavity-based AIDS-related lymphomas. Evolution of a new disease entity. Am J Clin Pathol 105 (2): 141-3, 1996.
36. Kirk O, Pedersen C, Cozzi-Lepri A, et al.: Non-Hodgkin lymphoma in HIV-infected patients in the era of highly active antiretroviral therapy. Blood 98 (12): 3406-12, 2001.
37. Ohno Y, Kosaka T, Muraoka I, et al.: Remission of primary low-grade gastric lymphomas of the mucosa-associated lymphoid tissue type in immunocompromised pediatric patients. World J Gastroenterol 12 (16): 2625-8, 2006.
38. Fedorova A, Mlyavaya T, Alexeichik A, et al.: Successful treatment of the HIV-associated Burkitt lymphoma in a three-year-old child. Pediatr Blood Cancer 47 (1): 92-3, 2006.
39. Loren AW, Porter DL, Stadtmauer EA, et al.: Post-transplant lymphoproliferative disorder: a review. Bone Marrow Transplant 31 (3): 145-55, 2003.
40. Harris NL, Jaffe ES, Diebold J, et al.: World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 17 (12): 3835-49, 1999.
41. Chadburn A, Cesarman E, Liu YF, et al.: Molecular genetic analysis demonstrates that multiple posttransplantation lymphoproliferative disorders occurring in one anatomic site in a single patient represent distinct primary lymphoid neoplasms. Cancer 75 (11): 2747-56, 1995.
42. Collins MH, Montone KT, Leahey AM, et al.: Autopsy pathology of pediatric posttransplant lymphoproliferative disorder. Pediatrics 107 (6): E89, 2001.
43. Claviez A, Meyer U, Dominick C, et al.: MALT lymphoma in children: a report from the NHL-BFM Study Group. Pediatr Blood Cancer 47 (2): 210-4, 2006.
44. Lorsbach RB, Shay-Seymore D, Moore J, et al.: Clinicopathologic analysis of follicular lymphoma occurring in children. Blood 99 (6): 1959-64, 2002.
45. Abla O, Sandlund JT, Sung L, et al.: A case series of pediatric primary central nervous system lymphoma: favorable outcome without cranial irradiation. Pediatr Blood Cancer 47 (7): 880-5, 2006.
46. Abla O, Weitzman S: Primary central nervous system lymphoma in children. Neurosurg Focus 21 (5): E8, 2006.
47. Akyuz C, Aydin GB, Cila A, et al.: Successful use of intraventricular and intravenous rituximab therapy for refractory primary CNS lymphoma in a child. Leuk Lymphoma 48 (6): 1253-5, 2007.
48. Windsor R, Stiller C, Webb D: Peripheral T-cell lymphoma in childhood: population-based experience in the United Kingdom over 20 years. Pediatr Blood Cancer 50 (4): 784-7, 2008.
49. Hutchison RE, Laver JH, Chang M, et al.: Non-anaplastic peripheral t-cell lymphoma in childhood and adolescence: a Children's Oncology Group study. Pediatr Blood Cancer 51 (1): 29-33, 2008.
50. Rosh JR, Gross T, Mamula P, et al.: Hepatosplenic T-cell lymphoma in adolescents and young adults with Crohn's disease: a cautionary tale? Inflamm Bowel Dis 13 (8): 1024-30, 2007.

Stage Information

The most widely used staging scheme for childhood non-Hodgkin lymphoma (NHL) is that of the St. Jude Children's Research Hospital (Murphy Staging).[1]

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 bone marrow and/or central nervous system (CNS) disease regardless of other sites of involvement.

Bone marrow involvement has been defined as 5% malignant cells in an otherwise normal bone marrow with normal peripheral blood counts and smears. Patients with lymphoblastic lymphoma with 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 any other NHL, the definition of CNS disease is any malignant cell present in the CSF regardless of cell count. The Berlin-Frankfurt-Munster (BFM) group analyzed the prevalence, clinical pattern, and outcome of CNS involvement in NHL in over 2,500 patients.[2] Overall, CNS involvement was diagnosed in 6% of patients. Involvement by cell type was as follows:

  • Burkitt lymphoma/leukemia: 8.8%
  • Precursor B-cell lymphoblastic lymphoma: 5.4%
  • Anaplastic large cell lymphoma: 3.3%
  • T-cell lymphoblastic lymphoma: 3.7%
  • Diffuse large B-cell lymphoma: 2.6%
  • Primary mediastinal large B-cell lymphoma: 0%

The probability of event-free survival at 6 years for CNS-positive patients was 64% compared with 86% for CNS-negative patients. Presence of CNS involvement did not impact outcome for T-cell lymphoblastic lymphoma patients, but had significant negative impact on patients with Burkitt lymphoma/leukemia.[2]

As with histologic classification, there exist several different staging schemes for childhood NHL; none is perfect. For example, in the French Society of Pediatric Oncology and most recent international French-American-British study for B-lineage NHL, group A is completely resected stage I and II disease; group C is disease with leukemic disease (>25% marrow involvement) and/or CNS disease; and group B consists of all other patients.[3,4] For B-lineage NHL, the BFM group treats according to four risk groups: R1 is completely resected disease; R2 is unresected disease or stage III disease with lactate dehydrogenase (LDH) less than 500 u/L; R3 is stage III and LDH concentrations of 500 to 1,000 u/L or leukemic disease (>25% marrow disease) with LDH levels higher than 1,000 u/L; and R4 is stage III/IV disease or leukemic disease with LDH levels higher than 1,000 u/L and/or CNS involvement.[5] In general, treatment for childhood NHL depends on localized versus disseminated disease. Localized disease is usually defined as stage I or II disease, while stage III or IV disease is generally considered disseminated.

References:

1. Murphy SB, Fairclough DL, Hutchison RE, et al.: Non-Hodgkin's lymphomas of childhood: an analysis of the histology, staging, and response to treatment of 338 cases at a single institution. J Clin Oncol 7 (2): 186-93, 1989.
2. Salzburg J, Burkhardt B, Zimmermann M, et al.: Prevalence, clinical pattern, and outcome of CNS involvement in childhood and adolescent non-Hodgkin's lymphoma differ by non-Hodgkin's lymphoma subtype: a Berlin-Frankfurt-Munster Group Report. J Clin Oncol 25 (25): 3915-22, 2007.
3. Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007.
4. Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007.
5. Reiter A, Schrappe M, Tiemann M, et al.: Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 94 (10): 3294-306, 1999.

Treatment Option Overview

Many of the improvements in childhood cancer survival have been made using combinations of known and/or new agents that have attempted to improve 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 clinical trials is available from the NCI Web site.

NHL in children is generally considered to be widely disseminated from the outset, even when apparently localized; as a result, combination chemotherapy is recommended for most patients.[1] There are two potentially life-threatening clinical situations that are often seen in children with NHL: (1) superior vena cava syndrome (or mediastinal tumor with airway obstruction), and (2) tumor lysis syndrome, most often seen in lymphoblastic and Burkitt or Burkitt-like NHL. These emergent situations should be anticipated in children with NHL and addressed immediately.

Patients with large mediastinal masses are at risk of cardiac or respiratory arrest during general anesthesia or heavy sedation.[2] Due to the risks of general anesthesia or heavy sedation, a careful physiologic and radiographic evaluation of the patient should be carried out and the least invasive procedure should be used to establish the diagnosis of lymphoma.[3,4] Bone marrow aspirate and biopsy should always be performed early in the work up of these patients. If a pleural effusion is present, a cytologic diagnosis is frequently possible using thoracentesis. In those children who present with peripheral adenopathy, a lymph node biopsy under local anesthesia and in an upright position may be possible.[5] In situations in which the above diagnostic procedures are not fruitful, consideration of a computed tomography–guided core needle biopsy should be contemplated. This procedure can frequently be carried out using light sedation and local anesthesia before proceeding to more invasive procedures. 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 general anesthesia or heavy sedation. In these situations, preoperative treatment with steroids or localized radiation therapy should be considered. Since preoperative treatment may affect the ability to obtain an accurate tissue diagnosis, a diagnostic biopsy should be obtained as soon as the risk of general anesthesia or heavy sedation is thought to be alleviated.

Tumor lysis syndrome results from rapid breakdown of malignant cells resulting in a number of metabolic abnormalities, most notably hyperuricemia, hyperkalemia, and hyperphosphatemia. Hyperhydration and allopurinol or rasburicase (urate oxidase) are essential components of therapy in all but patients with the most limited disease.[6,7,8] An initial prephase consisting of low-dose cyclophosphamide and vincristine does not obviate the need for allopurinol or rasburicase and hydration. Gastrointestinal bleeding, obstruction, and (rarely) perforation may occur. Hyperuricemia and tumor lysis syndrome, particularly when associated with ureteral obstruction, frequently result in life-threatening complications. Patients with NHL should be managed only in institutions having pediatric tertiary care facilities.

As opposed to the treatment of adults with NHL, the use of radiation therapy is limited in children with NHL. Early studies demonstrated that the routine use of radiation had no benefit for localized NHL.[9] It has been demonstrated that prophylactic central nervous system (CNS) radiation can be omitted in lymphoblastic lymphoma.[10] It has also been demonstrated that CNS radiation can be eliminated for patients with anaplastic large cell lymphoma and B-cell NHL, even for patients who present with CNS disease.[11,12] Further data to support the limited use of radiation in pediatric NHL comes from the Childhood Cancer Survivor Study.[13] This analysis demonstrated that radiation was a significant risk factor for secondary malignancy and death in long-term survivors.

Non-Hodgkin lymphoma (NHL) presenting as a secondary malignancy is rare in pediatrics. A retrospective review of the German Childhood Cancer Registry identified 11 (0.3%) of 2,968 newly diagnosed children older than 20 years with NHL as secondary malignancies.[14] In this small cohort, outcome was similar to patients with de novo NHL when treated with standard therapy.[14]

(Refer to the PDQ summary on Primary CNS Lymphoma Treatment for more information on treatment options for nonacquired immunodeficiency syndrome–related primary CNS lymphoma.)

References:

1. Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996.
2. Azizkhan RG, Dudgeon DL, Buck JR, et al.: Life-threatening airway obstruction as a complication to the management of mediastinal masses in children. J Pediatr Surg 20 (6): 816-22, 1985.
3. King DR, Patrick LE, Ginn-Pease ME, et al.: Pulmonary function is compromised in children with mediastinal lymphoma. J Pediatr Surg 32 (2): 294-9; discussion 299-300, 1997.
4. Shamberger RC, Holzman RS, Griscom NT, et al.: Prospective evaluation by computed tomography and pulmonary function tests of children with mediastinal masses. Surgery 118 (3): 468-71, 1995.
5. Prakash UB, Abel MD, Hubmayr RD: Mediastinal mass and tracheal obstruction during general anesthesia. Mayo Clin Proc 63 (10): 1004-11, 1988.
6. Pui CH, Mahmoud HH, Wiley JM, et al.: Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients With leukemia or lymphoma. J Clin Oncol 19 (3): 697-704, 2001.
7. Goldman SC, Holcenberg JS, Finklestein JZ, et al.: A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood 97 (10): 2998-3003, 2001.
8. Cairo MS, Bishop M: Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 127 (1): 3-11, 2004.
9. Link MP, Shuster JJ, Donaldson SS, et al.: Treatment of children and young adults with early-stage non-Hodgkin's lymphoma. N Engl J Med 337 (18): 1259-66, 1997.
10. Burkhardt B, Woessmann W, Zimmermann M, et al.: Impact of cranial radiotherapy on central nervous system prophylaxis in children and adolescents with central nervous system-negative stage III or IV lymphoblastic lymphoma. J Clin Oncol 24 (3): 491-9, 2006.
11. Seidemann K, Tiemann M, Schrappe M, et al.: Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 97 (12): 3699-706, 2001.
12. Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007.
13. Bluhm EC, Ronckers C, Hayashi RJ, et al.: Cause-specific mortality and second cancer incidence after non-Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. Blood 111 (8): 4014-21, 2008.
14. Landmann E, Oschlies I, Zimmermann M, et al.: Secondary non-Hodgkin lymphoma (NHL) in children and adolescents after childhood cancer other than NHL. Br J Haematol 143 (3): 387-94, 2008.

Localized Non-Hodgkin Lymphoma in Children and Adolescents

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Editorial Boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Patients with stage I and II disease have an excellent prognosis, regardless of histology. A Children's Cancer Group study demonstrated that pulsed chemotherapy with cyclophosphamide, vincristine, methotrexate, and prednisone (COMP) administered for 6 months for localized nonlymphoblastic non-Hodgkin lymphoma (NHL) was equivalent to 18 months of therapy with radiation to sites of disease, with more than 85% disease-free survival (DFS) and more than 90% overall survival.[1,2] Patients with lymphoblastic lymphoma had a much inferior outcome. A Pediatric Oncology Group (POG) study tested 9 weeks of short, pulsed chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), with or without radiation to involved sites and with or without 24 weeks of maintenance chemotherapy.[3] The results showed no benefit of radiation or maintenance chemotherapy, but the DFS for nonlymphoblastic lymphoma was superior to that of lymphoblastic lymphoma (90% vs. 60%).

For localized mature B-cell NHL (Burkitt or diffuse large B-cell lymphoma [DLBCL]), DFS is about 95%. The Berlin-Frankfurt Munster (BFM) group has treated risk group R1 (completely resected disease) with two cycles of multiagent chemotherapy (BFM-90).[4] For unresected stage I/II disease (R2), patients receive a cytoreductive phase followed by five cycles of chemotherapy.[4] In the BFM-90 study, it was shown that reducing the dose of methotrexate did not affect the results for localized disease.[4] In BFM-95, it was demonstrated for localized disease that prolonging duration of methotrexate infusion did not improve outcome.[5] The French Society of Pediatric Oncology (SFOP) and French-American-British (FAB) studies have treated all completely resected stage I and abdominal stage II (group A) with two cycles of multiagent chemotherapy and without intrathecal chemotherapy (SFOP-LMB-96).[6][Level of evidence: 2A] For unresected stage I/II disease (group B), the above-mentioned FAB study demonstrated that reducing duration of therapy to four cycles of chemotherapy following a cytoreduction phase and reducing the cumulative doses of cyclophosphamide and doxorubicin did not affect outcome.[7]

For localized lymphoblastic lymphoma (stage I/II disease), about 60% of patients can achieve long-term DFS with short, pulsed chemotherapy.[2,3] However, using an acute lymphoblastic leukemia approach with induction, consolidation, and maintenance for a total of 24 months, the BFM group (BFM-90/95) has shown more than 90% DFS for localized lymphoblastic lymphoma.[8,9]

For localized anaplastic large cell lymphoma (ALCL) (stage I/II disease), the best results have come from using pulsed chemotherapy similar to mature B-cell NHL therapy. In the POG study for localized lymphoma using three cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), a 5-year event-free survival of 88% for large cell lymphoma (ALCL and DLBCL) patients was reported.[3] The BFM group has used three cycles of chemotherapy following a cytoreductive prophase for completely resected stage I/II disease.[10] Primary cutaneous ALCL presents a particular problem. The diagnosis can be difficult to distinguish from more benign diseases such as lymphoid papulosis.[11] Many cutaneous ALCL are ALK-negative and may be treated successfully with surgical resection and/or local radiotherapy without systemic chemotherapy.[12] There are reports of surgery alone being curative for ALK-positive cutaneous ALCL, but extensive staging and vigilant follow-up is required.

Standard treatment options are based on histology; however, current data do not suggest superiority between regimens listed below for a specific histology.

Standard Treatment Options

LARGE CELL LYMPHOMA: both diffuse large B-cell lymphoma (DLBCL) and ALCL

  • Vincristine, doxorubicin, cyclophosphamide, prednisone, mercaptopurine, and methotrexate.[3]

DLBCL AND BURKITT LYMPHOMA

Completely resected disease:

  • NHL-BFM-95 (B-cell NHL): dexamethasone, cyclophosphamide, methotrexate (1 g/m2 over 4 hours), cytarabine, prednisolone (intrathecal [IT]), ifosfamide, etoposide, doxorubicin.[5]
  • FAB/LMB-96:FAB/LMB-96: cyclophosphamide, vincristine, doxorubicin, prednisone.[6][Level of evidence: 2A]

Incompletely resected disease:

  • NHL-BFM-95 (B-cell NHL): dexamethasone, cyclophosphamide, methotrexate (1 g/m2), cytarabine, prednisolone (IT), ifosfamide, etoposide, doxorubicin.[5]
  • FAB/LMB-96: cyclophosphamide, vincristine, prednisone, methotrexate (IT), high-dose methotrexate (3 g/m2), doxorubicin, cytarabine, etoposide. Reduced intensity arm for group B.[7]

LYMPHOBLASTIC LYMPHOMA

  • NHL-BFM-90/95 (lymphoblastic): prednisone, vincristine, daunorubicin, L-asparaginase, cyclophosphamide, cytarabine, mercaptopurine, methotrexate (intravenous and IT).[8,9]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage I childhood large cell lymphoma, stage I childhood small noncleaved cell lymphoma, stage I childhood lymphoblastic lymphoma, stage I childhood anaplastic large cell lymphoma, stage II childhood large cell lymphoma, stage II childhood small noncleaved cell lymphoma, stage II childhood lymphoblastic lymphoma and stage II childhood anaplastic large cell lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Meadows AT, Sposto R, Jenkin RD, et al.: Similar efficacy of 6 and 18 months of therapy with four drugs (COMP) for localized non-Hodgkin's lymphoma of children: a report from the Childrens Cancer Study Group. J Clin Oncol 7 (1): 92-9, 1989.
2. Anderson JR, Jenkin RD, Wilson JF, et al.: Long-term follow-up of patients treated with COMP or LSA2L2 therapy for childhood non-Hodgkin's lymphoma: a report of CCG-551 from the Childrens Cancer Group. J Clin Oncol 11 (6): 1024-32, 1993.
3. Link MP, Shuster JJ, Donaldson SS, et al.: Treatment of children and young adults with early-stage non-Hodgkin's lymphoma. N Engl J Med 337 (18): 1259-66, 1997.
4. Reiter A, Schrappe M, Tiemann M, et al.: Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 94 (10): 3294-306, 1999.
5. Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005.
6. Gerrard M, Cairo MS, Weston C, et al.: Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Br J Haematol 141 (6): 840-7, 2008.
7. Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007.
8. Reiter A, Schrappe M, Ludwig WD, et al.: Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report. Blood 95 (2): 416-21, 2000.
9. Burkhardt B, Woessmann W, Zimmermann M, et al.: Impact of cranial radiotherapy on central nervous system prophylaxis in children and adolescents with central nervous system-negative stage III or IV lymphoblastic lymphoma. J Clin Oncol 24 (3): 491-9, 2006.
10. Seidemann K, Tiemann M, Schrappe M, et al.: Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 97 (12): 3699-706, 2001.
11. Kumar S, Pittaluga S, Raffeld M, et al.: Primary cutaneous CD30-positive anaplastic large cell lymphoma in childhood: report of 4 cases and review of the literature. Pediatr Dev Pathol 8 (1): 52-60, 2005 Jan-Feb.
12. Hinshaw M, Trowers AB, Kodish E, et al.: Three children with CD30 cutaneous anaplastic large cell lymphomas bearing the t(2;5)(p23;q35) translocation. Pediatr Dermatol 21 (3): 212-7, 2004 May-Jun.

Disseminated Childhood B-cell Non-Hodgkin Lymphoma

Patients with disseminated mature B-lineage non-Hodgkin lymphoma (NHL) (Burkitt or Burkitt-like lymphoma and diffuse large B-cell lymphoma [DLBCL]) have an 80% to 90% long-term survival.[1,2,3] Unlike mature B-lineage NHL seen in adults, there is no difference in outcome based on histology (Burkitt, Burkitt-like, or DLBCL) with current therapy in pediatric trials.[1,2,3]

For the Berlin-Frankfurt-Munster (BFM) group, disseminated mature B-lineage NHL defined by R2 is unresected disease or stage III disease with lactate deyhdrogenase (LDH) levels lower than 500 u/L; R3 is stage III disease and LDH concentrations between 500 u/L and 1,000 u/L or leukemic disease (>25% blasts in marrow) with LDH levels lower than 1,000 u/L; R4 is stage III/IV disease or leukemic disease with LDH levels higher than 1,000 u/L and/or central nervous system (CNS) involvement.[1] All patients receive a cytoreductive prophase. R2 group patients receive four cycles of intensive chemotherapy; R3 patients receive five cycles of intensive chemotherapy; and R4 patients receive six cycles of intensive chemotherapy. In the BFM-90 study, it was demonstrated that increasing the dose and duration of infusion (24 hours) of methotrexate resulted in an improved outcome.[4] In the BFM-95 trial, it was shown that reducing the infusion time of methotrexate from 24 hours to 4 hours resulted in inferior outcome for R3 and R4 group patients.[1] Event-free survival (EFS) with best therapy in BFM-95 was more than 95% for R1 and R2 group patients and was 93% for R3 and R4 group patients. Inferior outcome was observed for patients with primary mediastinal B-cell lymphoma (50% 3-year EFS) and central nervous system (CNS) disease at presentation (70% 3-year EFS).[4] In the FAB/LMB-96 study, group B consists of all patients (stage I–IV) with unresected disease but excludes those with leukemic (>25% marrow involvement) and/or CNS involvement, while group C patients have leukemic and/or marrow involvement.[2,3] The outcome of group B patients, who had a greater than 20% response to cytoreductive prophase, was not affected by a reduction of the total dose of cyclophosphamide by 50% and elimination of one cycle of maintenance.[2] The 3-year EFS was 98%, 90%, and 86% for stage I/II, stage III, and stage IV (CNS-negative) patients, respectively, while patients with primary mediastinal B-cell lymphoma had a 3-year EFS of 70%.[2] In group C patients, reduction of therapy resulted in inferior outcome.[3] Patients with leukemic disease only, and no CNS disease, had a 3-year EFS of 90%, while patients with CNS disease at presentation had a 70% 3-year EFS.[3] This study identified response to prophase reduction as the most significant prognostic factor, with poor responders (i.e., <20% resolution of disease) having an EFS of 30%.[3] Both the BFM and FAB/LMB studies demonstrated that omission of craniospinal irradiation, even in patients presenting with CNS disease, does not affect outcome (FAB/LMB96, NHL-BFM 90).[1,2,3,4]

Involvement of the bone marrow may lead to confusion as to 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.[1,3] Poor prognostic factors for B-cell NHL include: high levels of LDH,[1,2,4] primary mediastinal disease,[1,2] CNS disease at presentation,[1,3] suboptimal response to cytoreductive prophase,[3] and age older than 15 years, which appears to be attributable primarily to patients with DLBCL.[1,5] Data suggest that secondary cytogenetic abnormalities, other than c-myc rearrangement, are associated with an inferior outcome.[6] The prognostic role of minimal residual disease (MRD) in the treatment of Burkitt leukemia remains unclear. Results from a single study suggest inferior outcome for patients with detectable MRD.[7] Testicular disease at diagnosis does not seem to confer poor prognosis.[8]

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 Treatment Option Overview section of this summary for more information.) For reduction of the complications of tumor lysis syndrome, current treatment regimens use a prophase of reduced intensity to cytoreduce patients;[1,2,3] however, this does not obviate the use of hyperhydration and allopurinol or rasburicase (urate oxidase). Hyperuricemia and tumor lysis syndrome, particularly when associated with ureteral obstruction, frequently result in life-threatening complications. Gastrointestinal bleeding, obstruction, and (rarely) perforation may occur. Patients with NHL should be managed only in institutions having pediatric tertiary care facilities.[9]

Rituximab is a mouse/human chimeric monoclonal antibody targeting the CD20 antigen. Among the lymphomas that occur in children, DLBCL and Burkitt lymphoma both express high levels of CD20.[10] Rituximab has been safely combined with standard doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP) chemotherapy and has been shown to improve outcome in a randomized trial of adults with DLBCL (CAN-NCIC-LY9).[11,12] In an adult study, rituximab has also been safely combined with an intensive chemotherapy regimen used to treat patients with Burkitt lymphoma.[13] At present, there are no data that rituximab improves outcome when added to current regimens used to treat pediatric NHL patients. A Children's Oncology Group (COG) pilot study (COG-ANHL01P1) is evaluating rituximab in combination with the intensive chemotherapy regimen based on the French LMB-89 protocol.

Standard Treatment Options

Current data do not suggest superiority for either of the following standard treatment options.

  • FAB/LMB-96: cyclophosphamide, vincristine, prednisone, methotrexate (IT), high-dose methotrexate, doxorubicin, cytarabine, etoposide. Reduced intensity arm for group B, and full intensity for group C.[2,3]
  • NHL-BFM 95: dexamethasone, cyclophosphamide, methotrexate, cytarabine, prednisolone (IT), ifosfamide, etoposide, vindesine, doxorubicin.[1]

Treatment Options Under Clinical Evaluation

  • COG-ANHL01P1: addition of rituximab to FAB/LMB-96–based therapy for stage III/IV (group B) and group C patients.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III childhood large cell lymphoma, stage III childhood small noncleaved cell lymphoma, stage IV childhood large cell lymphoma and stage IV childhood small noncleaved cell lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005.
2. Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007.
3. Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007.
4. Reiter A, Schrappe M, Tiemann M, et al.: Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 94 (10): 3294-306, 1999.
5. Burkhardt B, Zimmermann M, Oschlies I, et al.: The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol 131 (1): 39-49, 2005.
6. Onciu M, Schlette E, Zhou Y, et al.: Secondary chromosomal abnormalities predict outcome in pediatric and adult high-stage Burkitt lymphoma. Cancer 107 (5): 1084-92, 2006.
7. Mussolin L, Pillon M, Conter V, et al.: Prognostic role of minimal residual disease in mature B-cell acute lymphoblastic leukemia of childhood. J Clin Oncol 25 (33): 5254-61, 2007.
8. Dalle JH, Mechinaud F, Michon J, et al.: Testicular disease in childhood B-cell non-Hodgkin's lymphoma: the French Society of Pediatric Oncology experience. J Clin Oncol 19 (9): 2397-403, 2001.
9. Cairo MS, Bishop M: Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 127 (1): 3-11, 2004.
10. Perkins SL, Lones MA, Davenport V, et al.: B-Cell non-Hodgkin's lymphoma in children and adolescents: surface antigen expression and clinical implications for future targeted bioimmune therapy: a children's cancer group report. Clin Adv Hematol Oncol 1 (5): 314-7, 2003.
11. Coiffier B, Lepage E, Briere J, et al.: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346 (4): 235-42, 2002.
12. Pfreundschuh M, Trümper L, Osterborg A, et al.: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7 (5): 379-91, 2006.
13. Thomas DA, Faderl S, O'Brien S, et al.: Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer 106 (7): 1569-80, 2006.

Disseminated Childhood Lymphoblastic Lymphoma

Patients with disseminated lymphoblastic lymphoma have long-term survival rates higher than 80%.[1] Unlike other pediatric non-Hodgkin lymphoma (NHL), it has been shown that lymphoblastic lymphoma responds much better to leukemia therapy with 2 years of therapy than with shorter, intensive, pulsed chemotherapy regimens.[1,2,3] The best results to date come from the Berlin-Frankfurt-Munster (BFM) group. In the NHL-BFM-90 study, the 5-year disease-free survival was 90%, and there was no difference in outcome between stage III and stage IV patients.[1] Precursor B-cell lymphoblastic lymphoma appears to have similar results using the same therapy.[4] In the NHL-BFM-95 study, the prophylactic cranial radiation was omitted, and the intensity of induction therapy was decreased slightly. There were no significant increases in central nervous system (CNS) relapses, suggesting cranial radiation may be reserved for patients with CNS disease at diagnosis.[3] Of interest, the probability of 5-year event-free survival (EFS) rates was worse in BFM-95 than in BFM-90 (82% vs. 90% respectively). Although this difference was not statistically different, BFM-95 had a reduction of asparaginase and doxorubicin in induction, which may have affected outcome. It was proposed that the major difference in EFS between BFM-90 and BFM-95 resulted from the increased number of secondary malignancies observed in BFM-95.[3] A single-center study suggests that patients treated for lymphoblastic lymphoma have a higher incidence of secondary malignancy than do patients treated for other pediatric NHL; however, studies from the Children's Oncology Group and the Childhood Cancer Survivor Study Group do not support this finding.[5,6,7]

Involvement of the bone marrow may lead to confusion as to whether the patient has lymphoma or leukemia. Traditionally, patients with more than 25% marrow blasts are classified as having leukemia, and those with fewer than 25% marrow blasts are classified as having lymphoma. It is not yet clear whether these arbitrary definitions are biologically distinct or relevant for treatment design. All current therapies for advanced-stage lymphoblastic lymphoma have been derived from regimens designed for the treatment of acute lymphoblastic leukemia.

Mediastinal radiation is not necessary for patients with mediastinal masses, except in the emergency treatment of symptomatic superior vena caval obstruction or airway obstruction, where low-dose radiation is usually employed. (Refer to the Treatment Option Overview section of this summary for more information on such complications.) Because of the complexities of optimal therapeutic regimens and the possibility of toxic side effects, patients should be offered the opportunity to enter into a clinical trial. Information about ongoing clinical trials is available from the NCI Web site.

Standard Treatment Options

Current data do not suggest superiority for the following standard treatment options.

  • NHL-BFM-95: prednisone, dexamethasone, vincristine, daunorubicin, doxorubicin, L-asparaginase, cyclophosphamide, cytarabine, methotrexate, 6-mercaptopurine, 6-thioguanine, CNS radiation therapy for CNS-positive patients only.[1]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III childhood lymphoblastic lymphoma and stage IV childhood lymphoblastic lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Reiter A, Schrappe M, Ludwig WD, et al.: Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report. Blood 95 (2): 416-21, 2000.
2. Anderson JR, Jenkin RD, Wilson JF, et al.: Long-term follow-up of patients treated with COMP or LSA2L2 therapy for childhood non-Hodgkin's lymphoma: a report of CCG-551 from the Childrens Cancer Group. J Clin Oncol 11 (6): 1024-32, 1993.
3. Burkhardt B, Woessmann W, Zimmermann M, et al.: Impact of cranial radiotherapy on central nervous system prophylaxis in children and adolescents with central nervous system-negative stage III or IV lymphoblastic lymphoma. J Clin Oncol 24 (3): 491-9, 2006.
4. Burkhardt B, Zimmermann M, Oschlies I, et al.: The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol 131 (1): 39-49, 2005.
5. Leung W, Sandlund JT, Hudson MM, et al.: Second malignancy after treatment of childhood non-Hodgkin lymphoma. Cancer 92 (7): 1959-66, 2001.
6. Abromowitch M, Sposto R, Perkins S, et al.: Shortened intensified multi-agent chemotherapy and non-cross resistant maintenance therapy for advanced lymphoblastic lymphoma in children and adolescents: report from the Children's Oncology Group. Br J Haematol 143 (2): 261-7, 2008.
7. Bluhm EC, Ronckers C, Hayashi RJ, et al.: Cause-specific mortality and second cancer incidence after non-Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. Blood 111 (8): 4014-21, 2008.

Disseminated Childhood Anaplastic Large Cell Lymphoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Editorial Boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Children and adolescents with disseminated anaplastic large cell lymphoma (ALCL) have a disease-free survival of approximately 60% to 75%.[1,2,3,4] It is unclear which strategy is best for the treatment of disseminated ALCL. The German Berlin-Frankfurt-Munster (BFM) group has also used six cycles of intensive pulsed therapy, similar to their B-cell non-Hodgkin lymphoma (NHL) therapy (NHL-BFM-90).[2] The Pediatric Oncology Group (POG) trial POG 9317 demonstrated no benefit to methotrexate and high-dose cytarabine added to 52 weeks of cyclic chemotherapy.[3] The Italian Association of Pediatric Hematology/Oncology used a leukemia-like regimen for 24 months in LNH-92.[4] In ALCL-99, patients considered high risk (defined as mediastinal, skin, and/or visceral involvement) were eligible to be randomly assigned to 1 year of maintenance therapy of vinblastine or to no maintenance therapy.[5] Though uncommon, when leukemic peripheral blood involvement is present, it appears to be associated with an unfavorable prognosis.[6,7] One study suggested that the amount of tumor involvement as measured by polymerase chain reaction in the marrow is predictive for relapse.[8]

Standard Treatment Options

Current data do not suggest superiority for the following standard treatment options.

  • NHL-BFM 90: dexamethasone, cyclophosphamide, methotrexate, cytarabine, prednisolone (intrathecal [IT]), ifosfamide, etoposide, doxorubicin.[2]
  • APO: doxorubicin, prednisone, vincristine.[3]

Treatment Options Under Clinical Evaluation

  • COG-ANHL0131: The Children's Oncology Group (COG) is evaluating the contribution of vinblastine when added to standard therapy for children with newly diagnosed stage III and stage IV ALCL. Patients are randomly assigned to receive standard chemotherapy, which includes doxorubicin, prednisone, and vincristine; or to receive the same chemotherapy, substituting weekly vinblastine for vincristine during the consolidation phase of therapy. Vinblastine has been shown to be active as a single agent in patients with relapsed ALCL.[6]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III childhood anaplastic large cell lymphoma and stage IV childhood anaplastic large cell lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Brugières L, Deley MC, Pacquement H, et al.: CD30(+) anaplastic large-cell lymphoma in children: analysis of 82 patients enrolled in two consecutive studies of the French Society of Pediatric Oncology. Blood 92 (10): 3591-8, 1998.
2. Seidemann K, Tiemann M, Schrappe M, et al.: Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 97 (12): 3699-706, 2001.
3. Laver JH, Kraveka JM, Hutchison RE, et al.: Advanced-stage large-cell lymphoma in children and adolescents: results of a randomized trial incorporating intermediate-dose methotrexate and high-dose cytarabine in the maintenance phase of the APO regimen: a Pediatric Oncology Group phase III trial. J Clin Oncol 23 (3): 541-7, 2005.
4. Rosolen A, Pillon M, Garaventa A, et al.: Anaplastic large cell lymphoma treated with a leukemia-like therapy: report of the Italian Association of Pediatric Hematology and Oncology (AIEOP) LNH-92 protocol. Cancer 104 (10): 2133-40, 2005.
5. Le Deley M, Rosolen A, Reiter A, et al.: The impact of the association of vinblastine during induction chemotherapy and as maintenance treatment in children and adolescents with high-risk anaplastic large cell lymphoma: results of a randomized trial fo the EICNHL group.. [Abstract] Blood 112: 577.
6. Brugières L, Quartier P, Le Deley MC, et al.: Relapses of childhood anaplastic large-cell lymphoma: treatment results in a series of 41 children--a report from the French Society of Pediatric Oncology. Ann Oncol 11 (1): 53-8, 2000.
7. Grewal JS, Smith LB, Winegarden JD 3rd, et al.: Highly aggressive ALK-positive anaplastic large cell lymphoma with a leukemic phase and multi-organ involvement: a report of three cases and a review of the literature. Ann Hematol 86 (7): 499-508, 2007.
8. Damm-Welk C, Busch K, Burkhardt B, et al.: Prognostic significance of circulating tumor cells in bone marrow or peripheral blood as detected by qualitative and quantitative PCR in pediatric NPM-ALK-positive anaplastic large-cell lymphoma. Blood 110 (2): 670-7, 2007.

Recurrent Childhood Non-Hodgkin Lymphoma

For recurrent or refractory B-lineage non-Hodgkin lymphoma (NHL) or lymphoblastic lymphoma, survival is generally 10% to 20%.[1,2,3,4,5] For recurrent or refractory anaplastic large cell lymphoma, as many as 60% of patients can achieve long-term survival.[3] There is no current standard treatment option for patients with recurrent or progressive disease. The first goal is to try to control the disease. A Children's Cancer Group (CCG) study (CCG-5912) was able to achieve complete remission in 40% of NHL patients.[6] Radiation therapy may have a role in treating patients who have not had a complete response to therapy. The use of single-agent rituxumab as well as rituximab combined with standard cytotoxic chemotherapy has shown activity in the treatment of B-cell lymphoma patients.[7][Level of evidence: 3iiiDii][8] A Children's Oncology Group study using rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) to treat relapsed/refractory B-cell NHL (diffuse large B-cell lymphoma and Burkitt lymphoma) showed a complete remission/partial remission rate of 60%.[8][Level of evidence: 3iiA] If remission can be achieved, high-dose therapy and stem cell transplantation are usually pursued. The benefit of autologous versus allogeneic stem cell transplantation is unclear.[3,9,10,11,12,13] All patients with primary refractory or relapsed NHL should be considered for clinical trials.

Standard Treatment Options

  • Allogeneic or autologous bone marrow transplantation.[3,9,10,11,12,13]
  • DECAL: dexamethasone, etoposide, cisplatin, cytarabine, and L-asparaginase.[6]
  • ICE: ifosfamide, carboplatin, and etoposide.[14,15]
  • ICE + rituximab: (for B-cell lymphoma).[8]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent childhood non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Cairo MS, Sposto R, Perkins SL, et al.: Burkitt's and Burkitt-like lymphoma in children and adolescents: a review of the Children's Cancer Group experience. Br J Haematol 120 (4): 660-70, 2003.
2. Atra A, Gerrard M, Hobson R, et al.: Outcome of relapsed or refractory childhood B-cell acute lymphoblastic leukaemia and B-cell non-Hodgkin's lymphoma treated with the UKCCSG 9003/9002 protocols. Br J Haematol 112 (4): 965-8, 2001.
3. Attarbaschi A, Dworzak M, Steiner M, et al.: Outcome of children with primary resistant or relapsed non-Hodgkin lymphoma and mature B-cell leukemia after intensive first-line treatment: a population-based analysis of the Austrian Cooperative Study Group. Pediatr Blood Cancer 44 (1): 70-6, 2005.
4. Cairo MS, Sposto R, Hoover-Regan M, et al.: Childhood and adolescent large-cell lymphoma (LCL): a review of the Children's Cancer Group experience. Am J Hematol 72 (1): 53-63, 2003.
5. Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007.
6. Kobrinsky NL, Sposto R, Shah NR, et al.: Outcomes of treatment of children and adolescents with recurrent non-Hodgkin's lymphoma and Hodgkin's disease with dexamethasone, etoposide, cisplatin, cytarabine, and l-asparaginase, maintenance chemotherapy, and transplantation: Children's Cancer Group Study CCG-5912. J Clin Oncol 19 (9): 2390-6, 2001.
7. Attias D, Weitzman S: The efficacy of rituximab in high-grade pediatric B-cell lymphoma/leukemia: a review of available evidence. Curr Opin Pediatr 20 (1): 17-22, 2008.
8. Griffin TC, Weitzman S, Weinstein H, et al.: A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/refractory B-cell (CD20+) non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 52 (2): 177-81, 2009.
9. Levine JE, Harris RE, Loberiza FR Jr, et al.: A comparison of allogeneic and autologous bone marrow transplantation for lymphoblastic lymphoma. Blood 101 (7): 2476-82, 2003.
10. Ladenstein R, Pearce R, Hartmann O, et al.: High-dose chemotherapy with autologous bone marrow rescue in children with poor-risk Burkitt's lymphoma: a report from the European Lymphoma Bone Marrow Transplantation Registry. Blood 90 (8): 2921-30, 1997.
11. Sandlund JT, Bowman L, Heslop HE, et al.: Intensive chemotherapy with hematopoietic stem-cell support for children with recurrent or refractory NHL. Cytotherapy 4 (3): 253-8, 2002.
12. Gordon BG, Warkentin PI, Weisenburger DD, et al.: Bone marrow transplantation for peripheral T-cell lymphoma in children and adolescents. Blood 80 (11): 2938-42, 1992.
13. Woessmann W, Peters C, Lenhard M, et al.: Allogeneic haematopoietic stem cell transplantation in relapsed or refractory anaplastic large cell lymphoma of children and adolescents--a Berlin-Frankfurt-Münster group report. Br J Haematol 133 (2): 176-82, 2006.
14. Cairo MS, Shen V, Krailo MD, et al.: Prospective randomized trial between two doses of granulocyte colony-stimulating factor after ifosfamide, carboplatin, and etoposide in children with recurrent or refractory solid tumors: a children's cancer group report. J Pediatr Hematol Oncol 23 (1): 30-8, 2001.
15. Kung FH, Harris MB, Krischer JP: Ifosfamide/carboplatin/etoposide (ICE), an effective salvaging therapy for recurrent malignant non-Hodgkin lymphoma of childhood: a Pediatric Oncology Group phase II study. Med Pediatr Oncol 32 (3): 225-6, 1999.

Lymphoproliferative Disease Associated With Immunodeficiency in Children

Regardless of the etiology of the immune defect, immunodeficient children with lymphoma have a worse prognosis than does the general population with non-Hodgkin lymphoma (NHL).[1,2,3] If the disease is localized and amenable to complete surgical resection and/or radiation therapy, the outcome is quite favorable; however, most NHL in this population is disseminated and requires systemic cytotoxic therapy. These patients usually tolerate cytotoxic therapy poorly, with increased morbidity and mortality due to increased infectious complications and often increased end-organ toxicities. However, more indolent low-grade lymphomas (e.g., mucosa-associated lymphoid tissue [MALT] lymphomas) have developed in patients with common variable immunodeficiency or other immunodeficient states.[4,5] (Refer to the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information about MALT lymphomas.)

In the era of highly active antiretroviral therapy, children with human immunodeficiency virus and NHL should be treated with standard chemotherapy regimens for NHL, but careful attention to prophylaxis against and early detection of infection is warranted.[1,6] Patients with primary immunodeficiency can achieve complete and durable remissions with standard chemotherapy regimens for NHL, though again toxicity is increased.[2] Recurrences in these patients are common and may not represent the same clonal disease.[7] Immunologic correction through allogeneic stem cell transplantation is often required to prevent recurrences. Patients with DNA repair defects (e.g., ataxia-telangectasia) are particularly difficult to treat.[8] Cytotoxic agents produce much more toxicity and greatly increase the risk of secondary malignancies in these patients. Survival is rare at 5 years postdiagnosis. In posttransplant lymphoproliferative disease (PTLD), first-line therapy is the reduction of immunosuppression, as much as can be tolerated.[3,9] Rituximab, an anti-CD20 antibody, has been used with some success, but data for its use in children are sparse. In one study, ten children with PTLD were treated with standard chemotherapy regimens for pediatric NHL, with a resulting 70% disease-free survival (DFS).[10] Another study treated 36 children with PTLD who had failed other therapies with a low-dose chemotherapy regimen, resulting in 70% DFS.[6]

Standard Treatment Options

  • Standard chemotherapy regimens for specific histology.[1,2,7,10]
  • Low-dose cyclophosphamide and prednisone.[3]

Treatment Options Under Clinical Evaluation

  • COG-ANHL0221: Addition of rituximab to low-dose cyclophosphamide and prednisone.
  • Adoptive immunotherapy with either donor lymphocytes or ex vivo –generated Epstein-Barr virus–specific cytotoxic T-cells have been effective in treating PTLD following blood or bone marrow transplant;[11,12] however, this has not been shown to be as effective or practical in patients with PTLD following solid organ transplant.

Information about ongoing clinical trials is available from the NCI Web site.

References:

1. McClain KL, Joshi VV, Murphy SB: Cancers in children with HIV infection. Hematol Oncol Clin North Am 10 (5): 1189-201, 1996.
2. Seidemann K, Tiemann M, Henze G, et al.: Therapy for non-Hodgkin lymphoma in children with primary immunodeficiency: analysis of 19 patients from the BFM trials. Med Pediatr Oncol 33 (6): 536-44, 1999.
3. Gross TG, Bucuvalas JC, Park JR, et al.: Low-dose chemotherapy for Epstein-Barr virus-positive post-transplantation lymphoproliferative disease in children after solid organ transplantation. J Clin Oncol 23 (27): 6481-8, 2005.
4. Aghamohammadi A, Parvaneh N, Tirgari F, et al.: Lymphoma of mucosa-associated lymphoid tissue in common variable immunodeficiency. Leuk Lymphoma 47 (2): 343-6, 2006.
5. Ohno Y, Kosaka T, Muraoka I, et al.: Remission of primary low-grade gastric lymphomas of the mucosa-associated lymphoid tissue type in immunocompromised pediatric patients. World J Gastroenterol 12 (16): 2625-8, 2006.
6. Kirk O, Pedersen C, Cozzi-Lepri A, et al.: Non-Hodgkin lymphoma in HIV-infected patients in the era of highly active antiretroviral therapy. Blood 98 (12): 3406-12, 2001.
7. Hoffmann T, Heilmann C, Madsen HO, et al.: Matched unrelated allogeneic bone marrow transplantation for recurrent malignant lymphoma in a patient with X-linked lymphoproliferative disease (XLP). Bone Marrow Transplant 22 (6): 603-4, 1998.
8. Sandoval C, Swift M: Treatment of lymphoid malignancies in patients with ataxia-telangiectasia. Med Pediatr Oncol 31 (6): 491-7, 1998.
9. Green M, Michaels MG, Webber SA, et al.: The management of Epstein-Barr virus associated post-transplant lymphoproliferative disorders in pediatric solid-organ transplant recipients. Pediatr Transplant 3 (4): 271-81, 1999.
10. Hayashi RJ, Kraus MD, Patel AL, et al.: Posttransplant lymphoproliferative disease in children: correlation of histology to clinical behavior. J Pediatr Hematol Oncol 23 (1): 14-8, 2001.
11. Papadopoulos EB, Ladanyi M, Emanuel D, et al.: Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. N Engl J Med 330 (17): 1185-91, 1994.
12. Rooney CM, Smith CA, Ng CY, et al.: Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 92 (5): 1549-55, 1998.

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SEARCH THE NCI WEB SITE

The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.

There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.

FIND PUBLICATIONS

The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).

Changes to This Summary (08 / 04 / 2009)

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.

Extensive revisions were made to this summary.

More Information

ABOUT PDQ

  • PDQ® - NCI's Comprehensive Cancer Database.
    Full description of the NCI PDQ database.

ADDITIONAL PDQ SUMMARIES

  • PDQ® Cancer Information Summaries: Adult Treatment
    Treatment options for adult cancers.
  • PDQ® Cancer Information Summaries: Pediatric Treatment
    Treatment options for childhood cancers.
  • PDQ® Cancer Information Summaries: Supportive and Palliative Care
    Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.
  • PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)
    Tests or procedures that detect specific types of cancer.
  • PDQ® Cancer Information Summaries: Prevention
    Risk factors and methods to increase chances of preventing specific types of cancer.
  • PDQ® Cancer Information Summaries: Genetics
    Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.
  • PDQ® Cancer Information Summaries: Complementary and Alternative Medicine
    Information about complementary and alternative forms of treatment for patients with cancer.

IMPORTANT:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Date Last Modified: 2009-08-04

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