Childhood Non-Hodgkin Lymphoma Treatment (Professional)
General Information About Childhood Non-Hodgkin Lymphoma (NHL)
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the 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. 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.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For non-Hodgkin lymphoma (NHL), the 5-year survival rate has increased over the same time period from 45% to 88% in children younger than 15 years and from 47% to 77% for adolescents aged 15 to 19 years. 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 NHL) is the third most common childhood malignancy, and NHL accounts for approximately 7% of cancers in children younger than 20 years.[3,4] In the United States, about 800 new cases of NHL are diagnosed each year. The incidence is approximately ten cases per million people per year. The incidence of NHL observed in children and adolescents varies depending on age, histology, gender, and race. Although there is no sharp age peak, childhood NHL occurs most commonly in the second decade of life, and occurs infrequently in children younger than 3 years. NHL in infants is very rare (1% in Berlin-Frankfurt-Munster [BFM] trials from 1986 to 2002). The incidence of NHL is increasing overall, which is accounted for because of 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.
Childhood NHL is more common in males than in females, with the exception of primary mediastinal B-cell lymphoma, in which the incidence is almost the same in males and females.[3,6] A review of Surveillance, Epidemiology, and End Results (SEER) data on Burkitt lymphoma diagnosed in the United States between 1992 and 2008 revealed 2.5 cases/million person-years with more cases in males than in females (3.9:1.1). The incidence of diffuse large B-cell lymphoma increases with age in both males and females. The incidence of lymphoblastic lymphoma remains relatively constant across ages for both males and females.
The incidence and age distribution of specific types of NHL according to gender is described in Table 1.
Table 1. Incidence and Age Distribution of Specific Types of NHLa
|Incidence of NHL per million person-years|
|ALCL = anaplastic large cell lymphoma; DLBCL = diffuse large B-cell lymphoma; NHL = non-Hodgkin lymphoma.|
|a Adapted from Percy et al.|
|b In older adolescents, indolent and aggressive histologies (more commonly seen in adult patients) are beginning to be found.|
|Other (mostly ALCL)||2.3||3.3||4.3||7.8b||1.5||1.6||2.8||3.4b|
The incidence of NHL is higher in whites than in African Americans, and Burkitt lymphoma is more frequent in non-Hispanic whites (3.2 cases/million person-years) than in Hispanic whites (2.0 cases/million person-years).
Relatively little is known of the epidemiology of childhood NHL. However, immunodeficiency, both congenital and acquired (human immunodeficiency virus infection [HIV] or posttransplant immunodeficiency), increases the risk of NHL. Epstein-Barr virus (EBV) is associated with most cases of NHL seen in the immunodeficient population. Although 85% or more of Burkitt lymphoma is associated with the EBV in endemic Africa, approximately 15% of cases in Europe or the United States will have EBV detectable in the tumor tissue.
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 having a secondary malignancy. In this small cohort, outcome was similar to patients with de novo NHL when treated with standard therapy.
Prognostic Factors for Childhood NHL
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.
Prognostic factors for childhood NHL include the following:
- Age: NHL in infants is rare (1% in Berlin-Frankfurt-Munster [BFM] trials from 1986 to 2002). In this retrospective review, the outcome for infants was inferior compared with the outcome for older patients with NHL.
Adolescents have been reported to have inferior outcome compared with younger children.[10,11,12,13] A review of survival for various subtypes of NHL in children and adolescents between 1986 and 2007 has been reported by the BFM group. Event-free survival (EFS) was 79% for adolescents and 85% for children. This adverse affect of age appears to be most pronounced for adolescents with T-cell lymphoblastic lymphoma and diffuse large B-cell lymphoma compared with children with these diagnoses. The poorer outcome of patients older than 15 years appears to be attributable primarily to patients with diffuse large B-cell lymphoma. On the other hand, for patients with Burkitt and Burkitt-like lymphoma on the FAB LMB 96 (COG-C5961) clinical trial, adolescent age (= 15 years) was not an independent risk factor for inferior outcome, with 3-year EFS of 89% ▒ 1.0% for children younger than 15 years and 84% ▒ 3.4% for patients aged 15 years and older.
- Site of disease: In general, patients with low-stage 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.[15,16,17,18,19,20] Patients with NHL arising in bone have an excellent prognosis, regardless of histology.[21,22] Testicular involvement does not affect prognosis.[16,17,23] As opposed to adults, mediastinal involvement in children and adolescents with nonlymphoblastic NHL results in an inferior outcome.[10,14,15,18] For patients with primary mediastinal B-cell lymphoma, 3-year EFS is 50% to 70%,[14,15,18,24] and for patients with central nervous system (CNS) disease at presentation, the 3-year EFS is 70%.[14,18,25]
In anaplastic large cell lymphoma, a retrospective study by the European Intergroup for Childhood NHL (EICNHL) found a high-risk group of patients defined by involvement of mediastinum, skin, or viscera. An immune response against the ALK protein (i.e., anti-ALK antibody titer) appears to correlate with lower clinical stage and absence of these clinical risk features (mediastinal and visceral organ involvement) and predicts relapse risk but not overall survival. However, in the CCG-5941 study for anaplastic large cell lymphoma patients, only bone marrow involvement predicted inferior progression-free survival.[Level of evidence: 2A] Patients with leukemic involvement (>25% blasts in marrow) or CNS involvement at diagnosis require intensive therapy.[17,25,29] Although these intensive therapies have improved the outcome for patients with high-stage (stage III or IV) or advanced-stage disease, patients who present with CNS disease have the worst outcome.[17,25,29] The combination of CNS involvement and marrow disease appears to impact outcome the most for Burkitt lymphoma/leukemia. 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.
- Chromosomal abnormalities: Though data for cytogenetics is less robust than for childhood leukemia, some chromosomal abnormalities have been reported to have prognostic value.
- For pediatric Burkitt lymphoma patients, secondary cytogenetic abnormalities, other than c-myc rearrangement, are associated with an inferior outcome,[30,31] and cytogenetic abnormalities involving gain of 7q or deletion of 13q appear to have an inferior outcome on current chemotherapy protocols.[31,32]
- For pediatric patients with diffuse large B-cell lymphoma and chromosomal rearrangement at MYC (8q24), outcome appears to be lower.
- For pediatric patients with T-cell lymphoblastic lymphoma, loss of heterozygosity on chromosome 6q was associated with an increased risk of relapse.
- Tumor burden: A surrogate for tumor burden (i.e., elevated levels of lactate dehydrogenase) has been shown to be prognostic in many studies.[14,15,18,24]
More recently, detection of minimal disease at diagnosis or minimal residual disease (MRD) appears to be prognostic in most subtypes of childhood NHL. In a retrospective subset analysis, there was evidence that submicroscopic bone marrow and peripheral blood involvement, detected by reverse transcription-polymerase chain reaction (RT-PCR) from NPM-ALK, was found in approximately 50% of patients and correlated with clinical stage; marrow involvement detected by PCR was associated with a 50% cumulative incidence of relapse. The prognostic role of MRD in the treatment of Burkitt leukemia remains unclear.[35,36,37]
- Response to therapy: One of the most important predictive factors for Burkitt lymphoma/leukemia is response to the initial prophase treatment; poor responders (i.e., <20% resolution of disease) had an EFS of 30%. Results from two studies suggest inferior outcome for patients with Burkitt leukemia that had detectable MRD after induction chemotherapy.[35,36]
- Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.
- 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.
- 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 April 04, 2013.
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- 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.
- Jaffe ES, Harris NL, Stein H, et al.: Introduction and overview of the classification of the lymphoid neoplasms. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 157-66.
- Mbulaiteye SM, Biggar RJ, Bhatia K, et al.: Sporadic childhood Burkitt lymphoma incidence in the United States during 1992-2005. Pediatr Blood Cancer 53 (3): 366-70, 2009.
- 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.
- 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.
- 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.
- 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.
- Patte C, Auperin A, Michon J, et al.: The Société Franšaise d'Oncologie Pédiatrique LMB89 protocol: highly effective multiagent chemotherapy tailored to the tumor burden and initial response in 561 unselected children with B-cell lymphomas and L3 leukemia. Blood 97 (11): 3370-9, 2001.
- Burkhardt B, Oschlies I, Klapper W, et al.: Non-Hodgkin's lymphoma in adolescents: experiences in 378 adolescent NHL patients treated according to pediatric NHL-BFM protocols. Leukemia 25 (1): 153-60, 2011.
- Cairo MS, Sposto R, Gerrard M, et al.: Advanced stage, increased lactate dehydrogenase, and primary site, but not adolescent age (= 15 years), are associated with an increased risk of treatment failure in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB LMB 96 study. J Clin Oncol 30 (4): 387-93, 2012.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Le Deley MC, Reiter A, Williams D, et al.: Prognostic factors in childhood anaplastic large cell lymphoma: results of a large European intergroup study. Blood 111 (3): 1560-6, 2008.
- Ait-Tahar K, Damm-Welk C, Burkhardt B, et al.: Correlation of the autoantibody response to the ALK oncoantigen in pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with tumor dissemination and relapse risk. Blood 115 (16): 3314-9, 2010.
- Lowe EJ, Sposto R, Perkins SL, et al.: Intensive chemotherapy for systemic anaplastic large cell lymphoma in children and adolescents: final results of Children's Cancer Group Study 5941. Pediatr Blood Cancer 52 (3): 335-9, 2009.
- 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.
- 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.
- 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.
- Nelson M, Perkins SL, Dave BJ, et al.: An increased frequency of 13q deletions detected by fluorescence in situ hybridization and its impact on survival in children and adolescents with Burkitt lymphoma: results from the Children's Oncology Group study CCG-5961. Br J Haematol 148 (4): 600-10, 2010.
- 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.
- 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.
- 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.
- Mussolin L, Pillon M, d'Amore ES, et al.: Minimal disseminated disease in high-risk Burkitt's lymphoma identifies patients with different prognosis. J Clin Oncol 29 (13): 1779-84, 2011.
- Shiramizu B, Goldman S, Kusao I, et al.: Minimal disease assessment in the treatment of children and adolescents with intermediate-risk (Stage III/IV) B-cell non-Hodgkin lymphoma: a children's oncology group report. Br J Haematol 153 (6): 758-63, 2011.
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