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Childhood Non-Hodgkin Lymphoma Treatment (PDQ®)

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General Information About Childhood Non-Hodgkin Lymphoma (NHL)
Histopathologic and Molecular Classification of Childhood NHL
Stage Information for Childhood NHL
Treatment Option Overview for Childhood NHL
Mature B-cell NHL
Lymphoblastic Lymphoma
Anaplastic Large Cell Lymphoma
Lymphoproliferative Disease Associated With Immunodeficiency in Children
Rare NHL Occurring in Children
Changes to This Summary (05/27/2015)
About This PDQ Summary
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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. [1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive 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. [2] 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 therapy that is accepted as the best currently available therapy (standard therapy) with potentially better therapy. 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 website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. [1] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. [1] For non-Hodgkin lymphoma (NHL), the 5-year survival rate has increased over the same time period from 45% to 87% in children younger than 15 years and from 48% to 82% for adolescents aged 15 to 19 years. [1] 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.)

On the basis of immunophenotype, molecular biology, and clinical response to treatment, the vast majority of NHL cases occurring in childhood and adolescence fall into three categories:

  1. Mature B-cell NHL (Burkitt and Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and primary mediastinal B-cell lymphoma).

  2. Lymphoblastic lymphoma.

  3. Anaplastic large cell lymphoma.

Other rare types of pediatric NHL include the following:

Incidence

Lymphoma (Hodgkin lymphoma and NHL) is the third most common childhood malignancy, and NHL accounts for approximately 7% of cancers in children younger than 20 years in high-income countries. [3] [4]

The following factors affect the incidence of NHL in children and adolescents: [3]

Table 1. Incidence and Age Distribution of Specific Types of NHLa

 Incidence of NHL per Million Person-Years
 MalesFemales
Age (y)<55–910–1415–19<55–9 10–1415–19
Burkitt3.266.12.80.81.10.81.2
Lymphoblastic1.62.22.82.20.91.00.70.9
DLBCL0.51.22.56.10.60.71.44.9
Other (mostly ALCL)2.33.34.37.8b1.51.62.83.4b
ALCL = anaplastic large cell lymphoma; DLBCL = diffuse large B-cell lymphoma; NHL = non-Hodgkin lymphoma.
aAdapted from Percy et al. [3]
bIn older adolescents, indolent and aggressive histologies (more commonly seen in adult patients) are beginning to be found.

Epidemiology

Relatively little data have been published on the epidemiology of childhood NHL. However, known risk factors include the following:

Anatomy

Unlike adults with NHL who most often present with nodal disease, children typically have extranodal disease involving the mediastinum, abdomen, and/or head and neck, as well as marrow or CNS. [4] For example, in developed countries, Burkitt lymphoma/leukemia occurs in the abdomen (approximately 60% of cases), with 15% to 20% of cases arising in the head and neck. [11] [12] This high incidence of extranodal disease substantiates use of the Murphy staging system for pediatric NHL, as opposed to the Ann Arbor staging system.

Diagnostic Evaluation

The following tests and procedures are used to diagnose childhood NHL:

Prognosis and Prognostic Factors for Childhood NHL

In high-income countries and with current treatments, more than 80% of children and adolescents with NHL will survive at least 5 years, although outcome is variable depending on a number of factors, including clinical stage and histology. [13]

Prognostic factors for childhood NHL include the following:

Response to therapy

Response to therapy in pediatric lymphoma is one of the most important prognostic markers. Regardless of histology, pediatric NHL that is refractory to first-line therapy has a very poor prognosis. [14] [15] [16]

As opposed to acute leukemia, the prognostic value of minimal residual disease (MRD) following initiation of the therapy in pediatric NHL remains uncertain and requires further investigation.

Stage at diagnosis/minimal disseminated disease (MDD)

In general, patients with low-stage disease (i.e., single extra-abdominal/extrathoracic tumor or totally resected intra-abdominal tumor) have an excellent prognosis (a 5-year survival rate of approximately 90%), regardless of histology. [17] [19] [24] [25] [26] [27] Apart from this, the outcome by clinical stage, if the correct therapy is given, does not differ significantly, except for stage IV patients with CNS disease.

A surrogate for tumor burden (i.e., elevated levels of lactate dehydrogenase [LDH]) has been shown to be prognostic in many studies. [17] [25] [28] [29]

MDD is generally defined as submicroscopic bone marrow involvement that is present at diagnosis. MDD is generally detected by sensitive methods such as flow cytometry or reverse transcription–polymerase chain reaction (RT-PCR). Patients with morphologically involved bone marrow with more than 5% lymphoma cells are considered to have stage IV disease.

Sites of disease at diagnosis

In pediatric NHL, some sites of disease appear to have prognostic value, including the following:

Tumor biology

Age

NHL in infants is rare (1% in BFM trials from 1986 to 2002). [6] In this retrospective review, the outcome for infants was inferior compared with the outcome for older patients with NHL. [6]

Adolescents have been reported to have inferior outcome compared with younger children. [11] [13] [53] [54] This adverse effect of age appears to be most pronounced for adolescents with diffuse large B-cell lymphoma, and to a lesser degree T-cell lymphoblastic lymphoma, compared with younger children with these diagnoses. [13] [54] On the other hand, for patients with Burkitt and Burkitt-like lymphoma/leukemia on the FAB LMB 96 (COG-C5961) clinical trial, adolescent age (≥15 years) was not an independent risk factor for inferior outcome. [29]

Immune response to tumor

An immune response against the ALK protein (i.e., anti-ALK antibody titer) appeared to correlate with lower clinical stage and predicted relapse risk but not OS. [55] A study by the EICNHL, which combined the level of anti-ALK antibody with MDD, demonstrated that newly diagnosed anaplastic large cell lymphoma patients could be reliably stratified into three risk groups (low, intermediate, and all remaining patients), with a PFS of 28%, 68% and 93%, respectively (P < .0001). [38]

References:

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  2. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004.
  3. 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 May 26, 2015.
  4. Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996.
  5. Aka P, Kawira E, Masalu N, et al.: Incidence and trends in Burkitt lymphoma in northern Tanzania from 2000 to 2009. Pediatr Blood Cancer 59 (7): 1234-8, 2012.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. Patte C, Auperin A, Michon J, et al.: The Société Française 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.
  12. Lervat C, Auperin A, Patte C, et al.: Head and neck presentations of B-NHL and B-AL in children/adolescents: experience of the LMB89 study. Pediatr Blood Cancer 61 (3): 473-8, 2014.
  13. 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.
  14. 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.
  15. 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.
  16. Harris RE, Termuhlen AM, Smith LM, et al.: Autologous peripheral blood stem cell transplantation in children with refractory or relapsed lymphoma: results of Children's Oncology Group study A5962. Biol Blood Marrow Transplant 17 (2): 249-58, 2011.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. Stark B, Avigad S, Luria D, et al.: Bone marrow minimal disseminated disease (MDD) and minimal residual disease (MRD) in childhood T-cell lymphoblastic lymphoma stage III, detected by flow cytometry (FC) and real-time quantitative polymerase chain reaction (RQ-PCR). Pediatr Blood Cancer 52 (1): 20-5, 2009.
  23. Damm-Welk C, Mussolin L, Zimmermann M, et al.: Early assessment of minimal residual disease identifies patients at very high relapse risk in NPM-ALK-positive anaplastic large-cell lymphoma. Blood 123 (3): 334-7, 2014.
  24. 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.
  25. 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.
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  30. 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.
  31. Coustan-Smith E, Sandlund JT, Perkins SL, et al.: Minimal disseminated disease in childhood T-cell lymphoblastic lymphoma: a report from the children's oncology group. J Clin Oncol 27 (21): 3533-9, 2009.
  32. 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.
  33. 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.
  34. Williams D, Mori T, Reiter A, et al.: Central nervous system involvement in anaplastic large cell lymphoma in childhood: results from a multicentre European and Japanese study. Pediatr Blood Cancer 60 (10): E118-21, 2013.
  35. Gerrard M, Waxman IM, Sposto R, et al.: Outcome and pathologic classification of children and adolescents with mediastinal large B-cell lymphoma treated with FAB/LMB96 mature B-NHL therapy. Blood 121 (2): 278-85, 2013.
  36. Dunleavy K, Pittaluga S, Maeda LS, et al.: Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med 368 (15): 1408-16, 2013.
  37. 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.
  38. Mussolin L, Damm-Welk C, Pillon M, et al.: Use of minimal disseminated disease and immunity to NPM-ALK antigen to stratify ALK-positive ALCL patients with different prognosis. Leukemia 27 (2): 416-22, 2013.
  39. 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.
  40. 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.
  41. 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.
  42. 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.
  43. 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.
  44. 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.
  45. 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.
  46. Salaverria I, Philipp C, Oschlies I, et al.: Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults. Blood 118 (1): 139-47, 2011.
  47. Bonn BR, Rohde M, Zimmermann M, et al.: Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence. Blood 121 (16): 3153-60, 2013.
  48. 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.
  49. Stein H, Foss HD, Dürkop H, et al.: CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood 96 (12): 3681-95, 2000.
  50. Brugières L, Le Deley MC, Rosolen A, et al.: Impact of the methotrexate administration dose on the need for intrathecal treatment in children and adolescents with anaplastic large-cell lymphoma: results of a randomized trial of the EICNHL Group. J Clin Oncol 27 (6): 897-903, 2009.
  51. Alexander S, Kraveka JM, Weitzman S, et al.: Advanced stage anaplastic large cell lymphoma in children and adolescents: results of ANHL0131, a randomized phase III trial of APO versus a modified regimen with vinblastine: a report from the children's oncology group. Pediatr Blood Cancer 61 (12): 2236-42, 2014.
  52. Lamant L, McCarthy K, d'Amore E, et al.: Prognostic impact of morphologic and phenotypic features of childhood ALK-positive anaplastic large-cell lymphoma: results of the ALCL99 study. J Clin Oncol 29 (35): 4669-76, 2011.
  53. 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.
  54. 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.
  55. 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.

Histopathologic and Molecular Classification of Childhood NHL

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) classifies NHL according to the following features: [1]

Based on the WHO classification, the vast majority of NHL cases in childhood and adolescence fall into the following three categories:

  1. Mature B-cell NHL: Burkitt and Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and primary mediastinal B-cell lymphoma.

  2. Lymphoblastic lymphoma: Primarily precursor T-cell lymphoma and, less frequently, precursor B-cell lymphoma.

  3. Anaplastic large cell lymphoma: Mature peripheral T-cell/null-cell lymphomas. The null-cell variant is considered to be the same disease in which the cells have lost most of the T-cell antigens.

Refer to the following sections of this summary for more information about the tumor biology associated with each type of NHL:

WHO Classification for NHL

The WHO classification is the most widely used NHL classification and is shown in Table 2, with immunophenotype and common clinical and molecular findings in pediatric NHL. [1] [2]

Table 2. Major Histopathological Categories of Non-Hodgkin Lymphoma in Children and Adolescentsa

WHO ClassificationImmunophenotype Clinical Presentation Chromosome Abnormalities Genes Affected
Burkitt and Burkitt-like lymphoma/leukemiaMature B cellIntra-abdominal (sporadic), head and neck (non-jaw, sporadic), jaw (endemic), bone marrow, CNS 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 Mature B cell Nodal, abdominal, bone, primary CNS (when associated with immunodeficiency), mediastinalNo consistent cytogenetic abnormality identified  
Primary mediastinal B-cell lymphomaMature B cell, often CD30+Mediastinal, but may also have other nodal or extranodal disease (i.e., abdominal, often kidney)9p and 2p gainsJAK2, C-rel, SOCS1
Lymphoblastic lymphoma, precursor T-cell leukemia, or precursor B-cell lymphoma Pre-T cell Mediastinal, bone marrow MTS1/p16ink4a; deletion TAL1 t(1;14)(p34;q11), t(11;14)(p13;q11) TAL1, TCRAO, RHOMB1, HOX11, NOTCH1
Pre-B cell Skin, bone, head and neck     
Anaplastic large cell lymphoma, systemic CD30+ (Ki-1+) Variable, but systemic symptoms often prominent t(2;5)(p23;q35); less common variant translocations involving ALK ALK, NPM
T cell/null cell     
Anaplastic large cell lymphoma, cutaneous CD30+ (Ki-usually) Skin only; single or multiple lesionsLacks t(2;5) 
T cell     
+ = positive; CNS = central nervous system; WHO = World Health Organization.
aAdapted from Percy et al. [2]

Other types of lymphoma, such as the nonanaplastic large cell peripheral T-cell lymphomas (including T/NK lymphomas), cutaneous lymphomas, and indolent B-cell lymphomas (e.g., follicular lymphoma and marginal zone lymphoma), are more commonly seen in adults and occur rarely in children. The most recent WHO classification has designated pediatric follicular lymphoma and pediatric nodal marginal zone lymphoma as distinct entities from the counterparts observed in adults. [1]

Refer to the following PDQ summaries for more information about the treatment of NHL in adult patients:

References:

  1. 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.
  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 May 26, 2015.
  3. Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996.

Stage Information for Childhood NHL

The Ann Arbor staging system is used for all lymphomas in adults and for Hodgkin lymphoma in pediatrics. However, the Ann Arbor staging system has less prognostic value in pediatric non-Hodgkin lymphoma (NHL), primarily because of the high incidence of extranodal disease. Therefore, the most widely used staging schema for childhood NHL is that of the St. Jude Children’s Research Hospital (Murphy Staging). [1]

Role of Radiographic Imaging in Childhood NHL

Radiographic imaging is essential in the staging of patients with NHL. Ultrasound may be the preferred method for assessment of an abdominal mass, but computed tomography (CT) scan and, more recently, magnetic resonance imaging (MRI) have been used for staging. Radionucleotide bone scans may be considered for patients in whom bone involvement is suspected.

The role of functional imaging in pediatric NHL is controversial. Gallium scans have been replaced by fluorodeoxyglucose positron emission tomography (PET) scanning, which is now routinely performed at many centers. [2] A review of the revised International Workshop Criteria comparing CT imaging alone or CT together with PET imaging demonstrated that the combination of CT and PET imaging was more accurate than CT imaging alone. [3] [4]

While the International Harmonization Project for PET (now called the International Working Group) response criteria have been attempted in adults, the prognostic value of PET scanning for staging pediatric NHL remains under investigation. [2] [5] [6] Data support that PET identifies more abnormalities than CT scanning, [7] but it is unclear whether this should be used to upstage pediatric patients and change therapy. The International Working Group has updated their response criteria for malignant lymphoma to include PET, immunohistochemistry, and flow cytometry data. [4] [8]

St. Jude Children's Research Hospital (Murphy) Staging

Stage I childhood NHL

In stage I childhood NHL, a single tumor or nodal area is involved, excluding the abdomen and mediastinum.

Stage II childhood NHL

In stage II childhood NHL, disease extent is limited to a single tumor with regional node involvement, two or more tumors or nodal areas involved on one side of the diaphragm, or a primary gastrointestinal tract tumor (completely resected) with or without regional node involvement.

Stage III childhood NHL

In stage III childhood NHL, tumors or involved lymph node areas occur on both sides of the diaphragm. Stage III NHL also includes any primary intrathoracic (mediastinal, pleural, or thymic) disease, extensive primary intra-abdominal disease, or any paraspinal or epidural tumors.

Stage IV childhood NHL

In stage IV childhood NHL, tumors involve bone marrow and/or central nervous system (CNS), 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 who have more than 25% malignant cells in the bone marrow are usually considered to have leukemia and may be appropriately treated on leukemia clinical trials.

CNS disease in lymphoblastic lymphoma is defined by criteria similar to that used for acute lymphocytic leukemia (i.e., white blood cell count of at least 5/μL and malignant cells in the cerebrospinal fluid [CSF]). For other types of NHL, the definition of CNS disease is any malignant cell present in the CSF regardless of cell count. The Berlin-Frankfurt-Munster group analyzed the prevalence of CNS involvement in NHL in over 2,500 patients. Overall, CNS involvement was diagnosed in 6% of patients. CNS involvement (percentage of patients) according to NHL subtype was as follows: [9]

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. Juweid ME, Stroobants S, Hoekstra OS, et al.: Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 25 (5): 571-8, 2007.
  3. Brepoels L, Stroobants S, De Wever W, et al.: Hodgkin lymphoma: Response assessment by revised International Workshop Criteria. Leuk Lymphoma 48 (8): 1539-47, 2007.
  4. Cheson BD, Pfistner B, Juweid ME, et al.: Revised response criteria for malignant lymphoma. J Clin Oncol 25 (5): 579-86, 2007.
  5. Cheson BD: The International Harmonization Project for response criteria in lymphoma clinical trials. Hematol Oncol Clin North Am 21 (5): 841-54, 2007.
  6. Bakhshi S, Radhakrishnan V, Sharma P, et al.: Pediatric nonlymphoblastic non-Hodgkin lymphoma: baseline, interim, and posttreatment PET/CT versus contrast-enhanced CT for evaluation--a prospective study. Radiology 262 (3): 956-68, 2012.
  7. Cheng G, Servaes S, Zhuang H: Value of (18)F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography scan versus diagnostic contrast computed tomography in initial staging of pediatric patients with lymphoma. Leuk Lymphoma 54 (4): 737-42, 2013.
  8. Cheson BD, Fisher RI, Barrington SF, et al.: Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 32 (27): 3059-68, 2014.
  9. 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.

Treatment Option Overview for Childhood NHL

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 website.

NHL in children is generally considered to be widely disseminated at diagnosis, even when the tumor is apparently localized; as a result, combination chemotherapy is recommended for most patients. [1] Exceptions to this treatment strategy include the following:

In contrast to the treatment of adults with NHL, the use of radiation therapy is limited in children with NHL. Study results include the following:

Radiation therapy may have a role in treating patients who have not had a complete response to chemotherapy. Data to support limiting the use of radiation therapy in pediatric NHL come from the Childhood Cancer Survivor Study. [7] This analysis demonstrated that radiation was a significant risk factor for subsequent neoplasms and death in long-term survivors.

Treatment of NHL in childhood and adolescence has historically been based on histologic subtype of the disease. A study by the Children’s Cancer Group demonstrated that the outcome for lymphoblastic lymphoma was superior with longer acute lymphoblastic leukemia–like therapy, while nonlymphoblastic NHL (Burkitt lymphoma/leukemia) had superior outcome with short, intensive, pulsed therapy, whereas the large cell lymphoma outcome was similar with either approach. [8]

Outcome for recurrent NHL in children and adolescents remains very poor, with the exception of anaplastic large cell lymphoma. [9] [10] [11] [12] [13] All patients with primary refractory or relapsed NHL should be considered for clinical trials.

Table 3. Treatment Options for Childhood Non-Hodgkin Lymphoma (NHL)

Childhood NHL ClassificationTreatment Options
Mature B-cell NHL:
 Burkitt and Burkitt-like lymphoma/leukemiaNewly diagnosedSurgery (for stage I and II only)
Chemotherapy   
RecurrentChemotherapy with or without rituximab  
Allogeneic or autologous SCT   
 Diffuse large B-cell lymphomaNewly diagnosedSurgery (for stage I and II only)
Chemotherapy   
RecurrentChemotherapy with or without rituximab  
Allogeneic or autologous SCT   
 Primary mediastinal B-cell lymphomaChemotherapy and rituximab
Lymphoblastic lymphomaNewly diagnosedChemotherapy with or without cranial-spinal radiation therapy
RecurrentChemotherapy  
Allogeneic SCT   
Anaplastic large cell lymphomaNewly diagnosedSurgery followed by chemotherapy (for stage I)
Chemotherapy   
RecurrentChemotherapy  
Allogeneic or autologous SCT   
Lymphoproliferative disease associated with immunodeficiency in children:
 Lymphoproliferative disease associated with primary immunodeficiencyChemotherapy
Allogeneic SCT   
 HIV-associated NHLChemotherapy
 PTLDSurgery and reduction of immunosuppressive therapy, if possible
Rituximab alone   
Standard or slightly modified chemotherapy with or without rituximab (for B-cell PTLD)   
Low-dose chemotherapy with or without rituximab (for EBV-positive B-cell PTLD)   
Rare NHL occurring in children:
 Pediatric follicular lymphomaSurgery only
Chemotherapy   
 MALT lymphomaSurgery only
Radiation therapy   
Chemotherapy   
 Primary CNS lymphomaChemotherapy
 Peripheral T-cell lymphomaChemotherapy
Radiation therapy   
Allogeneic or autologous SCT   
 Cutaneous T-cell lymphomaNo standard treatments have been established
CNS = central nervous system; EBV = Epstein-Barr virus; MALT = mucosa-associated lymphoid tissue; PTLD = posttransplant lymphoproliferative disease; SCT = stem cell transplantation.

Medical Emergencies

The most common potentially life-threatening clinical situations, most often seen in lymphoblastic lymphoma and Burkitt or Burkitt-like lymphoma/leukemia, are the following:

Mediastinal masses

Patients with large mediastinal masses are at risk for tracheal compression, superior vena caval compression, large pleural and pericardial effusions, and right and left ventricular outflow compression. Thus, cardiac or respiratory arrest is a significant risk, particularly if the patient is placed in a supine position. [14]

Because of the risks of general anesthesia or heavy sedation, a careful physiologic and radiographic evaluation of the patient should be completed, and the least invasive procedure should be used to establish the diagnosis of lymphoma. [15] [16] The following procedures may be used:

In situations when the above procedures do not yield a diagnosis, use of a computed tomography (CT)-guided core needle biopsy should be considered. This procedure can frequently be performed using light sedation and local anesthesia before proceeding to more invasive procedures. Care should be taken to keep patients out of a supine position. Most procedures, including CT scans and echocardiograms, can be done with the patient on his or her side or prone. 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, less commonly, localized radiation therapy should be considered. Because preoperative treatment may affect the ability to obtain an accurate tissue diagnosis, a diagnostic biopsy should be obtained as soon as the risk of general anesthesia or heavy sedation is reduced.

Tumor lysis syndrome

Tumor lysis syndrome results from rapid breakdown of malignant cells, causing a number of metabolic abnormalities, most notably hyperuricemia, hyperkalemia, and hyperphosphatemia. Tumor lysis syndrome may present before the start of therapy.

Hyperhydration and allopurinol or rasburicase (urate oxidase) are essential components of therapy in all patients, except those with the most limited disease. [18] [19] [20] [21] [22] [23] In patients with G6PD deficiency, rasburicase may cause hemolysis or methemoglobinuria. An initial prephase consisting of low-dose cyclophosphamide and vincristine does not obviate the need for allopurinol or rasburicase and hydration.

Hyperuricemia and tumor lysis syndrome, particularly when associated with ureteral obstruction, frequently result in life-threatening complications.

Tumor Surveillance

Although the use of positron emission tomography (PET) to assess rapidity of response to therapy appears to have prognostic value in Hodgkin lymphoma and some types of NHL observed in adult patients, it remains under investigation in pediatric NHL. To date, there are insufficient data in pediatric NHL to support that early response to therapy assessed by PET has prognostic value.

Diagnosing relapsed disease based solely on imaging requires caution because false-positive results are common. [24] [25] [26] There are also data demonstrating that PET scanning can produce false-negative results. [27] A study of young adults with primary mediastinal B-cell lymphoma demonstrated that among 12 patients who had residual mediastinal masses at the end of therapy, 9 of the 12 had positive PET scans. Seven of these nine patients had the masses resected, but no viable tumor was found. [28] Before undertaking changes in therapy based on residual masses noted by imaging, a biopsy to prove residual disease is warranted.

References:

  1. Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996.
  2. 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.
  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. Sandlund JT, Pui CH, Zhou Y, et al.: Effective treatment of advanced-stage childhood lymphoblastic lymphoma without prophylactic cranial irradiation: results of St Jude NHL13 study. Leukemia 23 (6): 1127-30, 2009.
  5. 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.
  6. 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.
  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.
  8. 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.
  9. Brugières L, Pacquement H, Le Deley MC, et al.: Single-drug vinblastine as salvage treatment for refractory or relapsed anaplastic large-cell lymphoma: a report from the French Society of Pediatric Oncology. J Clin Oncol 27 (30): 5056-61, 2009.
  10. Mori T, Takimoto T, Katano N, et al.: Recurrent childhood anaplastic large cell lymphoma: a retrospective analysis of registered cases in Japan. Br J Haematol 132 (5): 594-7, 2006.
  11. Woessmann W, Zimmermann M, Lenhard M, et al.: Relapsed or refractory anaplastic large-cell lymphoma in children and adolescents after Berlin-Frankfurt-Muenster (BFM)-type first-line therapy: a BFM-group study. J Clin Oncol 29 (22): 3065-71, 2011.
  12. Mossé YP, Lim MS, Voss SD, et al.: Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study. Lancet Oncol 14 (6): 472-80, 2013.
  13. Pro B, Advani R, Brice P, et al.: Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol 30 (18): 2190-6, 2012.
  14. 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.
  15. 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.
  16. 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.
  17. Prakash UB, Abel MD, Hubmayr RD: Mediastinal mass and tracheal obstruction during general anesthesia. Mayo Clin Proc 63 (10): 1004-11, 1988.
  18. 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.
  19. 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.
  20. Cairo MS, Bishop M: Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 127 (1): 3-11, 2004.
  21. Cairo MS, Coiffier B, Reiter A, et al.: Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol 149 (4): 578-86, 2010.
  22. Galardy PJ, Hochberg J, Perkins SL, et al.: Rasburicase in the prevention of laboratory/clinical tumour lysis syndrome in children with advanced mature B-NHL: a Children's Oncology Group Report. Br J Haematol 163 (3): 365-72, 2013.
  23. Coiffier B, Altman A, Pui CH, et al.: Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 26 (16): 2767-78, 2008.
  24. Rhodes MM, Delbeke D, Whitlock JA, et al.: Utility of FDG-PET/CT in follow-up of children treated for Hodgkin and non-Hodgkin lymphoma. J Pediatr Hematol Oncol 28 (5): 300-6, 2006.
  25. Nakatani K, Nakamoto Y, Watanabe K, et al.: Roles and limitations of FDG PET in pediatric non-Hodgkin lymphoma. Clin Nucl Med 37 (7): 656-62, 2012.
  26. Ulaner GA, Lilienstein J, Gönen M, et al.: False-Positive [18F]fluorodeoxyglucose-avid lymph nodes on positron emission tomography-computed tomography after allogeneic but not autologous stem-cell transplantation in patients with lymphoma. J Clin Oncol 32 (1): 51-6, 2014.
  27. Picardi M, De Renzo A, Pane F, et al.: Randomized comparison of consolidation radiation versus observation in bulky Hodgkin's lymphoma with post-chemotherapy negative positron emission tomography scans. Leuk Lymphoma 48 (9): 1721-7, 2007.
  28. Dunleavy K, Pittaluga S, Maeda LS, et al.: Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med 368 (15): 1408-16, 2013.

Mature B-cell NHL

Burkitt and Burkitt-like Lymphoma/Leukemia

Incidence

Burkitt and Burkitt-like lymphoma/leukemia in the United States accounts for about 40% of childhood non-Hodgkin lymphoma (NHL) and exhibits a consistent, aggressive clinical behavior. [1] [2] [3] The overall incidence of Burkitt lymphoma/leukemia in the United States is 2.5 cases per 1 million person-years and is higher among boys than girls (3.9 vs. 1.1). [2] [4] (Refer to Table 1 for more information on the incidence of Burkitt lymphoma by age and gender distribution.)

Tumor biology

The malignant cells show a mature B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase. These malignant cells usually express surface immunoglobulin, most bearing a clonal surface immunoglobulin M with either kappa or lambda light chains. A variety of additional B-cell markers (e.g., CD19, CD20, CD22) are usually present, and most childhood Burkitt and Burkitt-like lymphoma/leukemia express CALLA (CD10). [1]

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 oncogene and immunoglobulin locus regulatory elements, resulting in the inappropriate expression of c-myc, a gene involved in cellular proliferation. [3] [5] [6] The presence of one of the variant translocations t(2;8) or t(8;22) does not appear to affect response or outcome. [7]

The distinction between Burkitt and Burkitt-like lymphoma/leukemia is controversial. Burkitt lymphoma/leukemia consists of uniform, small, noncleaved cells, whereas Burkitt-like lymphoma/leukemia is a highly disputed diagnosis among pathologists because of features that are consistent with diffuse large B-cell lymphoma. [8]

Cytogenetic evidence of c-myc rearrangement is the gold standard for diagnosis of Burkitt lymphoma/leukemia. For cases in which cytogenetic analysis is not available, the World Health Organization (WHO) has recommended that the Burkitt-like diagnosis be reserved for lymphoma resembling Burkitt lymphoma/leukemia or with more pleomorphism, large cells, and a proliferation fraction (i.e., MIB-1 or Ki-67 immunostaining) of 99% or greater. [1]

Studies have demonstrated that the vast majority of Burkitt-like or atypical Burkitt lymphoma/leukemia has a gene expression signature similar to Burkitt lymphoma/leukemia. [9] [10] Additionally, as many as 30% of pediatric diffuse large B-cell lymphoma cases will have a gene signature similar to Burkitt lymphoma/leukemia. [9] [11]

Clinical presentation

The most common primary sites of disease are the abdomen and the lymphatic tissue of Waldeyer ring. [3] [4] Other sites of involvement include testes, bone, skin, bone marrow, and central nervous system (CNS). While lung involvement does not tend to occur, pleural and peritoneal spread is seen.

Prognostic factors

Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information on prognostic factors for Burkitt lymphoma/leukemia.

Standard treatment options for Burkitt and Burkitt-like lymphoma/leukemia

The treatment of Burkitt and Burkitt-like lymphoma/leukemia is the same as treatment for diffuse large B-cell lymphoma. The following discussion is pertinent to the treatment of both types of childhood NHL.

Unlike mature B-lineage NHL seen in adults, there is no difference in outcome based on histology (Burkitt or Burkitt-like lymphoma/leukemia or diffuse large B-cell lymphoma). Pediatric Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma are clinically very aggressive and are treated with very intensive regimens. [12] [13] [14] [15] [16]

Tumor lysis syndrome is often present at diagnosis or after initiation of treatment. This emergent clinical situation should be anticipated and addressed before treatment is started. (Refer to the Tumor lysis syndrome section in the Treatment Option Overview for Childhood NHL section of this summary for more information.)

Current treatment strategies are based on risk stratification as described in Table 4. Involvement of the bone marrow may lead to confusion 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 leukemia. [12] [14]

Table 4. FAB/LMB and BFM Staging Schemas for B-cell NHL

 StratumDisease Manifestation
FAB/LMB International Study [13] [14] [17]ACompletely resected stage I and abdominal stage II
BaMultiple extra-abdominal sites 
Nonresected stage I and II, III, IV (marrow <25% blasts, no CNS disease)  
CMature B-cell ALL (>25% blasts in marrow) and/or CNS disease 
 
BFM Group [18]R1Completely resected stage I and abdominal stage II
R2Nonresected stage I or II and stage III with LDH <500 IU/L 
R3Stage III with LDH 500–999 IU/L 
Stage IV, B-ALL (>25% blasts), no CNS disease, and LDH <1,000 IU/L  
R4Stage III, IV, B-cell ALL with LDH >1,000 IU/L 
Any CNS disease  
ALL = acute lymphoblastic leukemia; BFM = Berlin-Frankfurt-Munster; CNS= central nervous system; FAB = French-American-British; LDH = lactate dehydrogenase; NHL = non-Hodgkin lymphoma.
aBased on results of the FAB-96/LMB study, a serum LDH level more than twice the upper limit of normal has been used to define a group B high-risk group in the open international B-NHL study ANHL1131 (NCT01595048). [13]

The following studies have contributed to the development of current treatment regimens for pediatric Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma.

Evidence (chemotherapy):

  1. The Berlin-Frankfurt-Munster (BFM) group has treated risk group R1 (completely resected disease) with two cycles of multiagent chemotherapy (GER-GPOH-NHL-BFM-90 and GER-GPOH-NHL-BFM-95). [12] [18] For unresected stage I or stage II disease (R2), patients received a cytoreductive phase followed by five cycles of chemotherapy. [12] [18]

  2. In the NHL-BFM-95 study, reducing the infusion time of methotrexate from 24 hours to 4 hours for R3 and R4 group patients resulted in less mucositis, but inferior outcome. [12]

  3. The French Society of Pediatric Oncology and French-American-British (FAB) studies have treated completely resected stage I and abdominal stage II (group A) patients with two cycles of multiagent chemotherapy, without intrathecal chemotherapy (COG-C5961 [FAB/LMB-96]). [17][Level of evidence: 2A]

  4. For unresected stage I through IV disease (group B), the above-mentioned FAB study demonstrated that reducing the duration of therapy to four cycles of chemotherapy after a cytoreduction phase and reducing the cumulative doses of cyclophosphamide and doxorubicin did not affect outcome. [13]

  5. In group C patients in the FAB study, reduction in cumulative dose of therapy and number of maintenance cycles resulted in inferior outcome. [14]

Both the BFM and FAB/LMB studies demonstrated that omission of craniospinal irradiation, even in patients presenting with CNS disease, does not affect outcome (COG-C5961 [FAB/LMB-96] and NHL-BFM-90 [GER-GPOH-NHL-BFM-90]). [12] [13] [14] [18]

Rituximab is a mouse/human chimeric monoclonal antibody targeting the CD20 antigen. Burkitt lymphoma/leukemia and diffuse large B-cell lymphoma both express high levels of CD20. [5] 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 diffuse large B-cell lymphoma (CAN-NCIC-LY9). [19] In children, a single-agent phase II study of rituximab performed by the BFM group showed activity in Burkitt lymphoma/leukemia. [20][Level of evidence: 2Div] A Children's Oncology Group (COG) pilot study (COG-ANHL01P1) added rituximab to baseline chemotherapy with FAB/LMB-96 therapy in patients with stage III and stage IV B-cell NHL. Compared with chemotherapy-only protocols, toxicity was similar, despite a trend toward higher peak rituximab levels in younger patients. [21]; [15][Level of evidence: 3iiiA] The contribution of rituximab in pediatric B-cell lymphoma is being evaluated in an international randomized phase III trial. [22]

Standard treatment options for Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma are described in Table 5.

Table 5. Standard Treatment Options for Burkitt and Burkitt-like Lymphoma/Leukemia and Diffuse Large B-cell Lymphoma

Trial StratumDisease Manifestations Treatment
POG-8314/POG-8719/POG 9219 [23] Completely resected stage I and IIThree cycles of outpatient chemotherapy (no radiation or maintenance therapy).
 
COG-C5961 (FAB/LMB-96) [13] [14] [17]ACompletely resected stage I and abdominal stage II Two cycles of chemotherapy.
BMultiple extra-abdominal sites Prephase plus four cycles of chemotherapy (reduced-intensity arm). 
Nonresected stage I and II, III, IV    
Marrow <25% blasts   
No CNS disease    
CMature B-cell ALL (>25% blasts in marrow) and/or CNS disease Prephase + eight cycles of chemotherapy (full intensity arm). 
 
GER-GPOH-NHL-BFM-95 [12] [18]R1 Completely resected stage I and abdominal stage IITwo cycles of chemotherapy.
R2 Nonresected stage I/II and stage III with LDH <500 IU/LPrephase plus four cycles of chemotherapy (4-hour methotrexate infusion). 
R3 Stage III with LDH 500–999 IU/LPrephase plus five cycles of chemotherapy (24-hour methotrexate infusion). 
Stage IV, B-cell ALL (>25% blasts) and LDH <1,000 IU/L    
No CNS disease    
R4 Stage III, IV, B-cell ALL with LDH >1,000 IU/LPrephase plus six cycles of chemotherapy (24-hour methotrexate infusion). 
Any CNS disease    
ALL = acute lymphoblastic leukemia; BFM = Berlin-Frankfurt-Munster; CNS= central nervous system; COG = Children's Oncology Group; LDH = lactate dehydrogenase; NHL = non-Hodgkin lymphoma; POG = Pediatric Oncology Group.

Treatment options for recurrent Burkitt and Burkitt-like lymphoma/leukemia

There is no standard treatment option for patients with recurrent or progressive disease.

Treatment options for recurrent Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma include the following:

  1. DECAL (dexamethasone, etoposide, cisplatin, cytarabine, and L-asparaginase). [24]

  2. ICE (ifosfamide, carboplatin, and etoposide) plus rituximab (for B-cell lymphoma). [25]

  3. Allogeneic or autologous stem cell transplantation (SCT). [26] [27]

For recurrent or refractory B-lineage NHL, survival is generally 10% to 20%. [14] [28] [29] [30] [31] Chemoresistance makes remission difficult to achieve.

Evidence (rituximab therapy):

  1. The COG conducted a study of 20 patients (14 of whom had Burkitt lymphoma/leukemia) using rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) to treat relapsed/refractory B-cell NHL (Burkitt lymphoma/leukemia and diffuse large B-cell lymphoma). [25][Level of evidence: 3iiA]

If remission can be achieved, high-dose therapy and SCT remains the best option for survival. However, the benefit of autologous versus allogeneic SCT is unclear. [26] [30] [32] [33]; [34][Level of evidence: 2A]; [35][Level of evidence: 3iiiDii]

Patients not in remission at time of transplant do significantly worse. [26] [34] The very poor outcome of patients whose disease is refractory to salvage chemotherapy suggests that a transplant option should not be pursued in these patients. [36]

(Refer to the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation).

Evidence (SCT therapy):

  1. An analysis of the Center for International Blood and Marrow Transplant Research data demonstrated the following: [26]

  2. A small, single-center, prospective study used autologous transplantation followed by reduced-intensity allogeneic SCT in relapsed NHL. [27]

Treatment options under clinical evaluation for Burkitt and Burkitt-like lymphoma/leukemia

Treatment options under clinical evaluation for Burkitt and Burkitt-like lymphoma/leukemia include the following:

Information about ongoing clinical trials is available from the NCI website.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood Burkitt lymphoma, stage I childhood small noncleaved cell lymphoma, stage II childhood small noncleaved cell lymphoma, stage III childhood small noncleaved cell lymphoma, stage IV childhood small noncleaved cell lymphoma and recurrent 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.

Diffuse Large B-cell Lymphoma

Primary mediastinal B-cell lymphoma, previously considered a subtype of diffuse large B-cell lymphoma, is now a separate entity in the most recent WHO classification. (Refer to the Primary Mediastinal B-cell Lymphoma section of this summary for more information.)

Incidence

Diffuse large B-cell lymphoma is a mature B-cell neoplasm that represents 10% to 20% of pediatric NHL. [2] [3] [37] Diffuse large B-cell lymphoma occurs more frequently during the second decade of life than during the first decade. [2] [38] (Refer to Table 1 for more information on the incidence of diffuse large B-cell lymphoma by age and gender distribution.)

Tumor biology

The WHO classification system does not recommend subclassification of diffuse large B-cell lymphoma based on morphologic variants (e.g., immunoblastic, centroblastic). [39]

Diffuse large B-cell lymphoma in children and adolescents differs biologically from diffuse large B-cell lymphoma in adults in the following ways:

Clinical presentation

Pediatric diffuse large B-cell lymphoma may present in a manner clinically similar to Burkitt or Burkitt-like lymphoma/leukemia, although it is more often localized and less often involves the bone marrow or CNS. [37] [38] [45] (Refer to the Clinical presentation section in the Burkitt and Burkitt-like Lymphoma/Leukemia section of this summary for more information.)

Prognostic factors

Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information on prognostic factors for diffuse large B-cell lymphoma.

Treatment options for diffuse large B-cell lymphoma

As in Burkitt and Burkitt-like lymphoma/leukemia, current treatment strategies are based on risk stratification, as described in Table 4. The treatment of diffuse large B-cell lymphoma is the same as the treatment of Burkitt and Burkitt-like lymphoma/leukemia. Refer to the Standard treatment options for Burkitt and Burkitt-like lymphoma/leukemia section of this summary for information on the treatment of diffuse large B-cell lymphoma.

Treatment options for recurrent diffuse large B-cell lymphoma

The treatment of recurrent diffuse large B-cell lymphoma is the same as treatment of recurrent Burkitt and Burkitt-like lymphoma/leukemia. Refer to the Treatment options for recurrent Burkitt and Burkitt-like lymphoma/leukemia section of this summary for more information.

Treatment options under clinical evaluation for diffuse large B-cell lymphoma

The treatment options under clinical evaluation for diffuse large B-cell lymphoma are the same as those for the treatment of Burkitt and Burkitt-like lymphoma/leukemia. Refer to the Treatment options under clinical evaluation for Burkitt and Burkitt-like lymphoma/leukemia section of this summary for more information.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood diffuse large cell lymphoma, stage I childhood large cell lymphoma, stage II childhood large cell lymphoma, stage III childhood large cell lymphoma, stage IV childhood large cell lymphoma and recurrent childhood 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.

Primary Mediastinal B-cell Lymphoma

Incidence

In the pediatric population, primary mediastinal B-cell lymphoma is predominantly seen in older adolescents, accounting for 1% to 2% of all pediatric NHL cases. [38] [46] [47] [48]

Tumor biology

Primary mediastinal B-cell lymphoma was previously considered a subtype of diffuse large B-cell lymphoma, but is now a separate entity in the most recent WHO classification. [49] These tumors arise in the mediastinum from thymic B-cells and show a diffuse large cell proliferation with sclerosis that compartmentalizes neoplastic cells.

Primary mediastinal B-cell lymphoma can be very difficult to distinguish morphologically from the following types of lymphoma:

Primary mediastinal B-cell lymphoma is associated with distinctive chromosomal aberrations (gains in chromosome 9p and 2p in regions that involve JAK2 and c-rel, respectively) [47] [48] and commonly shows inactivation of SOCS1 by either mutation or gene deletion. [50] [51] Primary mediastinal B-cell lymphoma has a distinctly different gene expression profile from diffuse large B-cell lymphoma, but its gene expression profile has features similar to those seen in Hodgkin lymphoma. [52] [53]

Clinical presentation

As the name would suggest, primary mediastinal B-cell lymphoma occurs in the mediastinum. The tumor can be locally invasive (e.g., pericardial and lung extension) and can be associated with the superior vena caval syndrome. The tumor can disseminate outside the thoracic cavity with nodal and extranodal involvement, with predilection to the kidneys; however, CNS and marrow involvement are exceedingly rare. [49]

Prognostic factors

Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information on prognostic factors for primary mediastinal B-cell lymphoma.

Treatment options for primary mediastinal B-cell lymphoma

Treatment options for primary mediastinal B-cell lymphoma include the following:

  1. Dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R)

Pediatric and adolescent patients with stage III primary mediastinal large B-cell lymphoma did significantly worse on the FAB/LMB-96 (NCT00002757) study, with a 5-year EFS of 66% compared with 85% for adolescents with nonmediastinal diffuse large B-cell lymphoma. [54][Level of evidence: 2A] Similarly on NHL-BFM-95, patients with primary mediastinal B-cell lymphoma had an EFS of 50% at 3 years. [12] However, a study of young adults treated with DA-EPOCH-R showed excellent disease-free survival. [55]

Evidence (DA-EPOCH-R):

  1. A single-arm study in young adults utilized the DA-EPOCH-R regimen (usually six cycles) with filgrastim and no radiation therapy. [55][Level of evidence: 2A]

  2. A single-arm modification of DA-EPOCH-R (usually six cycles with filgrastim and no radiation therapy) was completed by the BFM group, in which the cumulative doxorubicin dose was kept at 360 mg/m2 and intrathecal chemotherapy was added. [56]

Treatment options under clinical evaluation for primary mediastinal B-cell lymphoma

Treatment options under clinical evaluation for primary mediastinal B-cell lymphoma include the following:

Information about ongoing clinical trials is available from the NCI website.

References:

  1. Leoncini L, Raphael M, Stein H: Burkitt lymphoma. 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 262-4.
  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 May 26, 2015.
  3. Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996.
  4. 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.
  5. 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.
  6. Miles RR, Cairo MS, Satwani P, et al.: Immunophenotypic identification of possible therapeutic targets in paediatric non-Hodgkin lymphomas: a children's oncology group report. Br J Haematol 138 (4): 506-12, 2007.
  7. Gualco G, Weiss LM, Harrington WJ Jr, et al.: Nodal diffuse large B-cell lymphomas in children and adolescents: immunohistochemical expression patterns and c-MYC translocation in relation to clinical outcome. Am J Surg Pathol 33 (12): 1815-22, 2009.
  8. Kluin PM, Harris NL, Stein H: B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. 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 265-6.
  9. 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.
  10. Dave SS, Fu K, Wright GW, et al.: Molecular diagnosis of Burkitt's lymphoma. N Engl J Med 354 (23): 2431-42, 2006.
  11. Deffenbacher KE, Iqbal J, Sanger W, et al.: Molecular distinctions between pediatric and adult mature B-cell non-Hodgkin lymphomas identified through genomic profiling. Blood 119 (16): 3757-66, 2012.
  12. 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.
  13. 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.
  14. 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.
  15. Goldman S, Smith L, Anderson JR, et al.: Rituximab and FAB/LMB 96 chemotherapy in children with Stage III/IV B-cell non-Hodgkin lymphoma: a Children's Oncology Group report. Leukemia 27 (5): 1174-7, 2013.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. Meinhardt A, Burkhardt B, Zimmermann M, et al.: Phase II window study on rituximab in newly diagnosed pediatric mature B-cell non-Hodgkin's lymphoma and Burkitt leukemia. J Clin Oncol 28 (19): 3115-21, 2010.
  21. Barth MJ, Goldman S, Smith L, et al.: Rituximab pharmacokinetics in children and adolescents with de novo intermediate and advanced mature B-cell lymphoma/leukaemia: a Children's Oncology Group report. Br J Haematol 162 (5): 678-83, 2013.
  22. Goldman S, Smith L, Galardy P, et al.: Rituximab with chemotherapy in children and adolescents with central nervous system and/or bone marrow-positive Burkitt lymphoma/leukaemia: a Children's Oncology Group Report. Br J Haematol 167 (3): 394-401, 2014.
  23. 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.
  24. 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.
  25. 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.
  26. Gross TG, Hale GA, He W, et al.: Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents. Biol Blood Marrow Transplant 16 (2): 223-30, 2010.
  27. Satwani P, Jin Z, Martin PL, et al.: Sequential myeloablative autologous stem cell transplantation and reduced intensity allogeneic hematopoietic cell transplantation is safe and feasible in children, adolescents and young adults with poor-risk refractory or recurrent Hodgkin and non-Hodgkin lymphoma. Leukemia 29 (2): 448-55, 2015.
  28. 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.
  29. 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.
  30. 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.
  31. 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.
  32. 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.
  33. 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.
  34. Harris RE, Termuhlen AM, Smith LM, et al.: Autologous peripheral blood stem cell transplantation in children with refractory or relapsed lymphoma: results of Children's Oncology Group study A5962. Biol Blood Marrow Transplant 17 (2): 249-58, 2011.
  35. Andion M, Molina B, Gonzalez-Vicent M, et al.: High-dose busulfan and cyclophosphamide as a conditioning regimen for autologous peripheral blood stem cell transplantation in childhood non-Hodgkin lymphoma patients: a long-term follow-up study. J Pediatr Hematol Oncol 33 (3): e89-91, 2011.
  36. Fujita N, Mori T, Mitsui T, et al.: The role of hematopoietic stem cell transplantation with relapsed or primary refractory childhood B-cell non-Hodgkin lymphoma and mature B-cell leukemia: a retrospective analysis of enrolled cases in Japan. Pediatr Blood Cancer 51 (2): 188-92, 2008.
  37. Reiter A, Klapper W: Recent advances in the understanding and management of diffuse large B-cell lymphoma in children. Br J Haematol 142 (3): 329-47, 2008.
  38. 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.
  39. Stein H, Warnke RA, Chan WC: Diffuse large B-cell lymphoma (DLBCL), NOS. 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 233-7.
  40. 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.
  41. 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.
  42. Klapper W, Kreuz M, Kohler CW, et al.: Patient age at diagnosis is associated with the molecular characteristics of diffuse large B-cell lymphoma. Blood 119 (8): 1882-7, 2012.
  43. 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.
  44. Salaverria I, Philipp C, Oschlies I, et al.: Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults. Blood 118 (1): 139-47, 2011.
  45. 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.
  46. 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.
  47. 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.
  48. Oschlies I, Burkhardt B, Salaverria I, et al.: Clinical, pathological and genetic features of primary mediastinal large B-cell lymphomas and mediastinal gray zone lymphomas in children. Haematologica 96 (2): 262-8, 2011.
  49. 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.
  50. 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.
  51. 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.
  52. 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.
  53. 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.
  54. Gerrard M, Waxman IM, Sposto R, et al.: Outcome and pathologic classification of children and adolescents with mediastinal large B-cell lymphoma treated with FAB/LMB96 mature B-NHL therapy. Blood 121 (2): 278-85, 2013.
  55. Dunleavy K, Pittaluga S, Maeda LS, et al.: Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med 368 (15): 1408-16, 2013.
  56. Woessmann W, Lisfeld J, Burkhardt B, et al.: Therapy in primary mediastinal B-cell lymphoma. N Engl J Med 369 (3): 282, 2013.

Lymphoblastic Lymphoma

Incidence

Lymphoblastic lymphoma comprises approximately 20% of childhood non-Hodgkin lymphoma (NHL). [1] [2] [3] (Refer to Table 1 for more information on the incidence of lymphoblastic lymphoma by age and gender distribution.)

Tumor Biology

Lymphoblastic lymphomas are usually positive for terminal deoxynucleotidyl transferase, with more than 75% having a T-cell immunophenotype and the remainder having a precursor B-cell phenotype. [3] [4]

As opposed to pediatric acute lymphoblastic leukemia (ALL), chromosomal abnormalities and the molecular biology of pediatric lymphoblastic lymphoma are not well characterized. The Berlin-Frankfurt-Munster (BFM) group reported that loss of heterozygosity at chromosome 6q was observed in 12% of patients and NOTCH1 mutations were seen in 60% of patients, but NOTCH1 mutations are rarely seen in patients with loss of heterozygosity in 6q16. [5] [6]

Clinical Presentation

As many as 75% of patients with T-cell lymphoblastic lymphoma will present with an anterior mediastinal mass, which may manifest as dyspnea, wheezing, stridor, dysphagia, or swelling of the head and neck.

Pleural and/or pericardial effusions may be present, and the involvement of lymph nodes, usually above the diaphragm, may be a prominent feature. There may also be involvement of bone, skin, bone marrow, central nervous system (CNS), abdominal organs (but rarely bowel), and occasionally other sites, such as lymphoid tissue of Waldeyer ring, testes, bone, or subcutaneous tissue. Abdominal involvement is less than what is observed in Burkitt lymphoma/leukemia.

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 T-cell ALL, and those with fewer than 25% marrow blasts are considered to have stage IV T-cell lymphoblastic lymphoma. The World Health Organization (WHO) classifies lymphoblastic lymphoma as the same disease as ALL. [7] The debate remains as to whether they truly represent the same disease. It is not yet clear whether these arbitrary definitions are biologically distinct or relevant for treatment design.

Prognostic Factors

Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information on prognostic factors for lymphoblastic lymphoma.

Standard Treatment Options for Lymphoblastic Lymphoma

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

Standard treatment options for lymphoblastic lymphoma include the following:

  1. GER-GPOH-NHL-BFM-95: Prednisone, dexamethasone, vincristine, daunorubicin, doxorubicin, L-asparaginase, cyclophosphamide, cytarabine, methotrexate, 6-mercaptopurine, 6-thioguanine, [8] and CNS radiation therapy for CNS-positive patients only. Treatment duration for T-cell and B-cell precursor lymphoblastic lymphoma is 24 months. [9] [10]

  2. COG-A5971 (NCT00004228): Prednisone, dexamethasone, vincristine, daunorubicin, doxorubicin, L-asparaginase, cyclophosphamide, cytarabine, methotrexate, 6-mercaptopurine, and 6-thioguanine. [11]
    1. Stage I or II (arm A0; localized disease): Modified Children's Cancer Group (CCG) BFM regimen (prednisone, dexamethasone, vincristine, daunorubicin, doxorubicin, L-asparaginase, cyclophosphamide, cytarabine, methotrexate, 6-mercaptopurine, 6-thioguanine, and reduced number of intrathecal treatments during maintenance).

    2. Stage III or IV (2 × 2 randomization):
        First randomization
      • Arm A1 (disseminated disease, no CNS disease): Modified CCG BFM regimen without intensification. No high-dose methotrexate administered during the interim maintenance phase, but intrathecal therapy is administered throughout the maintenance phase.

      • Arm B1 (disseminated disease, CNS-positive disease): GER-GPOH-NHL-BFM-95 regimen without intensification and without intrathecal therapy during maintenance.

        Second randomization
      • Arm A2 (disseminated disease, no CNS disease): Modified CCG BFM regimen (arm A1) with intensified induction.

      • Arm B2 (disseminated disease, CNS-positive disease): GER-GPOH-NHL-BFM-95 regimen (arm B1) with intensified induction and radiation therapy to the CNS.


    Equivalent outcome was observed for arms A1, B1, A2, and B2.


Patients with low-stage (stage I or stage II) lymphoblastic lymphoma have long-term disease-free survival (DFS) rates of about 60% with short, pulsed chemotherapy followed by 6 months of maintenance, with an overall survival (OS) greater than 90%. [12] [13] However, with the use of an ALL approach and induction, consolidation, and maintenance therapy for a total of 24 months, DFS rates higher than 90% have been reported for children with low-stage lymphoblastic lymphoma. [9] [10] [11]

Patients with high-stage (stage III or stage IV) lymphoblastic lymphoma have long-term survival rates higher than 80%. [8] [9] [10] Mediastinal radiation is not necessary for patients with mediastinal masses, except in the emergency treatment of symptomatic superior vena caval obstruction or airway obstruction. In these cases, either corticosteroid therapy or low-dose radiation is usually employed. (Refer to the Mediastinal masses section of the Treatment Option Overview for Childhood NHL section of this summary for more information.)

Evidence (high-stage treatment regimens for lymphoblastic lymphoma):

  1. In the GER-GPOH-NHL-BFM-90 study, the 5-year DFS was 90%, and there was no difference in outcome between stage III and stage IV patients. [9] Precursor B-cell lymphoblastic lymphoma appeared to have similar results using the same therapy. [2]

  2. In the GER-GPOH-NHL-BFM-95 study, the prophylactic cranial radiation was omitted, and the intensity of induction therapy was decreased slightly. [10]

  3. A trial (A5971 [NCT00004228]) of stage III and stage IV lymphoblastic lymphoma patients evaluated two strategies for CNS prophylaxis, without the use of CNS irradiation. Patients were randomly assigned to high-dose methotrexate in interim maintenance (BFM-95) or intrathecal chemotherapy throughout maintenance (CCG-BFM). [8][Level of evidence: 1iiA]

The Pediatric Oncology Group conducted a trial to test the effectiveness of the addition of high-dose methotrexate in T-cell ALL and T-cell lymphoblastic lymphoma. In the lymphoma patients, high-dose methotrexate did not demonstrate benefit. In the small cohort (n = 66) of lymphoma patients who did not receive high-dose methotrexate, the 5-year EFS was 88%. [14][Level of evidence: 1iiA] Of note, all of these patients received prophylactic craniospinal radiation therapy, which has been demonstrated not to be required in T-cell lymphoblastic lymphoma patients. [8] [10]

In addition to the NHL-BFM-95 trial, a single-center study reported that patients treated for lymphoblastic lymphoma had a higher incidence of subsequent neoplasms than did patients treated for other pediatric NHL. [15] However, studies from the Children's Oncology Group (COG) and the Childhood Cancer Survivor Study Group do not support this finding. [8] [16] [17]

Treatment Options for Recurrent Lymphoblastic Lymphoma

For recurrent or refractory lymphoblastic lymphoma, reports of survival range from 10% to 40%. [16] [18]; [19] [20][Level of evidence: 3iiiA] As with Burkitt lymphoma/leukemia, chemoresistant disease is common.

There are no standard treatment options for patients with recurrent or progressive disease.

Treatment options for recurrent lymphoblastic lymphoma include the following:

  1. DECAL (dexamethasone, etoposide, cisplatin, cytarabine, and L-asparaginase). [21]

  2. ICE (ifosfamide, carboplatin, and etoposide). [22]

  3. Allogeneic stem cell transplantation (SCT). [23]

Evidence (treatment of recurrent lymphoblastic lymphoma):

  1. A COG phase II study of nelarabine (compound 506U78) as a single agent demonstrated a response rate of 40%. [24]

  2. A BFM study showed a 14% OS for patients relapsing after BFM front-line therapy and all patients who survived had undergone an allogeneic SCT. [20]

  3. A Center for International Blood and Marrow Transplant Research analysis demonstrated that EFS was significantly worse using an autologous (4%) versus allogeneic (40%) donor stem cell source, with all failures resulting from progressive disease. [23]

Treatment Options Under Clinical Evaluation for Lymphoblastic Lymphoma

Treatment options under clinical evaluation for lymphoblastic lymphoma include the following:

Information about ongoing clinical trials is available from the NCI website.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I childhood lymphoblastic lymphoma, stage II childhood lymphoblastic lymphoma, stage III childhood lymphoblastic lymphoma, stage IV childhood lymphoblastic lymphoma and recurrent 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. 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 May 26, 2015.
  2. 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.
  3. Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996.
  4. 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.
  5. Bonn BR, Rohde M, Zimmermann M, et al.: Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence. Blood 121 (16): 3153-60, 2013.
  6. 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.
  7. 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.
  8. Termuhlen AM, Smith LM, Perkins SL, et al.: Disseminated lymphoblastic lymphoma in children and adolescents: results of the COG A5971 trial: a report from the Children's Oncology Group. Br J Haematol 162 (6): 792-801, 2013.
  9. 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.
  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. Termuhlen AM, Smith LM, Perkins SL, et al.: Outcome of newly diagnosed children and adolescents with localized lymphoblastic lymphoma treated on Children's Oncology Group trial A5971: a report from the Children's Oncology Group. Pediatr Blood Cancer 59 (7): 1229-33, 2012.
  12. 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.
  13. 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.
  14. Asselin BL, Devidas M, Wang C, et al.: Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404). Blood 118 (4): 874-83, 2011.
  15. Leung W, Sandlund JT, Hudson MM, et al.: Second malignancy after treatment of childhood non-Hodgkin lymphoma. Cancer 92 (7): 1959-66, 2001.
  16. 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.
  17. 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.
  18. 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.
  19. Mitsui T, Mori T, Fujita N, et al.: Retrospective analysis of relapsed or primary refractory childhood lymphoblastic lymphoma in Japan. Pediatr Blood Cancer 52 (5): 591-5, 2009.
  20. Burkhardt B, Reiter A, Landmann E, et al.: Poor outcome for children and adolescents with progressive disease or relapse of lymphoblastic lymphoma: a report from the berlin-frankfurt-muenster group. J Clin Oncol 27 (20): 3363-9, 2009.
  21. 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.
  22. 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.
  23. Gross TG, Hale GA, He W, et al.: Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents. Biol Blood Marrow Transplant 16 (2): 223-30, 2010.
  24. Berg SL, Blaney SM, Devidas M, et al.: Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group. J Clin Oncol 23 (15): 3376-82, 2005.

Anaplastic Large Cell Lymphoma

Incidence

Anaplastic large cell lymphoma accounts for approximately 10% of childhood non-Hodgkin lymphoma (NHL) cases. [1] (Refer to Table 1 for more information on the incidence of anaplastic large cell lymphoma by age and gender distribution.)

Tumor Biology

While the predominant immunophenotype of anaplastic large cell lymphoma is mature T-cell, null-cell disease (i.e., no T-cell, B-cell, or natural killer [NK]-cell surface antigen expression) does occur. The World Health Organization (WHO) classifies anaplastic large cell lymphoma as a subtype of peripheral T-cell lymphoma. [2]

All anaplastic large cell lymphoma cases are CD30-positive. More than 90% of pediatric anaplastic large cell lymphoma cases have a chromosomal rearrangement involving the ALK gene. About 85% of these chromosomal rearrangements will be t(2;5)(p23;q35), leading to the expression of the fusion protein NPM-ALK; the other 15% of cases are comprised of variant ALK translocations. [3] Anti-ALK immunohistochemical staining pattern is quite specific for the type of ALK translocation. Cytoplasm and nuclear ALK staining is associated with NPM-ALK fusion protein, whereas cytoplasmic staining only of ALK is associated with the variant ALK translocations. [3]

In adults, ALK-positive anaplastic large cell lymphoma is viewed differently from other peripheral T-cell lymphomas because prognosis tends to be superior. [4] Also, adult ALK-negative anaplastic large cell lymphoma patients have an inferior outcome compared with patients who have ALK-positive disease. [5] In children, however, this difference in outcome between ALK-positive and ALK-negative disease has not been demonstrated. In addition, no correlation has been found between outcome and the specific ALK-translocation type. [6] [7] [8]

In a European series of 375 children and adolescents with systemic ALK-positive anaplastic large cell lymphoma, the presence of a small cell or lymphohistiocytic component was observed in 32% of patients and was significantly associated with a high risk of failure in the multivariate analysis, controlling for clinical characteristics (hazard ratio, 2.0; P = .002). [7] The prognostic implication of the small cell variant of anaplastic large cell lymphoma was also shown in the COG-ANHL0131 study, despite a different chemotherapy backbone. [8]

Clinical Presentation

Clinically, systemic anaplastic large cell lymphoma has a broad range of presentations. These include involvement of lymph nodes and a variety of extranodal sites, particularly skin and bone and, less often, gastrointestinal tract, lung, pleura, and muscle. Involvement of the central nervous system (CNS) and bone marrow is uncommon.

Anaplastic large cell lymphoma is often associated with systemic symptoms (e.g., fever, weight loss) and a prolonged waxing and waning course, making diagnosis difficult and often delayed. Patients with anaplastic large cell lymphoma may present with signs and symptoms consistent with hemophagocytic lymphohistiocytosis. [9]

There is a subgroup of anaplastic large cell lymphoma with leukemic peripheral blood involvement. These patients usually exhibit significant respiratory distress with diffuse lung infiltrates or pleural effusions and have hepatosplenomegaly. [10] [11]

Prognostic Factors

Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information on prognostic factors for anaplastic large cell lymphoma.

Standard Treatment Options for Anaplastic Large Cell Lymphoma

Children and adolescents with high-stage (stage III or IV) anaplastic large cell lymphoma have a disease-free survival of approximately 60% to 75%. [12] [13] [14] [15] [16] [17]

It is unclear which treatment strategy is best for anaplastic large cell lymphoma. Current data do not suggest superiority of one treatment regimen over another for these standard treatment options.

Commonly used treatment regimens include the following:

  1. POG-8314/POG-8719/POG 9219: Three cycles of chemotherapy (no radiation or maintenance therapy) for stage I and stage II disease. [18]

  2. GER-GPOH-NHL-BFM-90: Prephase plus three cycles of chemotherapy (only for completely resected disease). [13]

  3. APO: Doxorubicin, prednisone, and vincristine. [14] This regimen can be administered in the outpatient setting. The duration of therapy is 52 weeks and the cumulative dose of doxorubicin in 300 mg/m2. No alkylator therapy is given.

  4. FRE-IGR-ALCL99: Dexamethasone, cyclophosphamide, ifosfamide, etoposide, doxorubicin, intravenous (IV) methotrexate (3 g/m2 arm), cytarabine, prednisolone, and vinblastine. [19] This regimen usually requires hospitalization for administration. The total duration of therapy is 5 months and the cumulative dose of doxorubicin is 150 mg/m2.

Evidence (treatment of anaplastic large cell lymphoma):

  1. The POG-9219 study for low-stage lymphoma used three cycles of doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP). [18]

  2. The FRE-IGR-ALCL99 trial used three cycles of chemotherapy after cytoreductive prophase for patients with stage I completely resected disease. The therapy for patients without complete resection was the same as the therapy for patients with disseminated disease. [20][Level of evidence: 2A]

  3. The German Berlin-Frankfurt-Munster (BFM) group used six cycles of intensive pulsed therapy, similar to their B-cell NHL therapy (GER-GPOH-NHL-BFM-90 [NHL-BFM-90]). [13] [21] [22]; [19][Level of evidence: 1iiA] Building on these results, the European Intergroup for Childhood NHL group conducted the FRE-IGR-ALCL99 study (based on the GER-GPOH-NHL-BFM-90 regimen).

  4. COG-ANHL0131 (NCT00059839) showed that the addition of vinblastine to the doxorubicin, prednisone, and vincristine (APO) regimen increased toxicity, but did not improve the survival. [8]

  5. The earlier Pediatric Oncology Group (POG) trial (POG-9317) demonstrated no benefit of adding methotrexate and high-dose cytarabine to 52 weeks of the APO regimen. [14]

  6. The Italian Association of Pediatric Hematology/Oncology group used a leukemia-like regimen for 24 months in LNH-92, with similar results as other regimens, although the duration of first remission was prolonged by the longer therapy. [15]

  7. The CCG-5941 study tested an approach similar to LNH-92, with more intensive induction and consolidation with maintenance for 1 year total duration of therapy, with similar outcome and similar significant increase in hematologic toxicity. [16][Level of evidence: 2A]

CNS involvement in anaplastic large cell lymphoma is rare at diagnosis. In an international study of systemic childhood anaplastic large cell lymphoma, 12 of 463 patients (2.6%) had CNS involvement, three of whom had isolated CNS disease (primary CNS lymphoma). For the CNS-positive group who received multiagent chemotherapy, including high-dose methotrexate, cytarabine, and intrathecal treatment, at a median follow-up of 4.1 years, the EFS was 50% (95% confidence interval, 25%–75%) and OS was 74% (45%–91%). The role of cranial radiation therapy has been difficult to assess. [23]

Treatment Options for Recurrent Anaplastic Large Cell Lymphoma

As opposed to mature B-cell or lymphoblastic lymphoma, the prognosis for recurrent or refractory anaplastic large cell lymphoma is 40% to 60%. [24] [25] [26]

There is no standard approach for the treatment of recurrent/refractory anaplastic large cell lymphoma.

Treatment options for recurrent anaplastic large cell lymphoma include the following:

  1. DECAL (dexamethasone, etoposide, cisplatin, cytarabine, and L-asparaginase). [27]

  2. ICE (ifosfamide, carboplatin, and etoposide). [28]

  3. Vinblastine. [29]

  4. Allogeneic or autologous stem cell transplantation (SCT). [30]

Chemotherapy, followed by autologous SCT or allogeneic SCT if remission can be achieved, has been employed in this setting. [25] [26] [30] [31]

Evidence (autologous vs. allogeneic SCT):

  1. A retrospective study of relapsed or refractory anaplastic large cell lymphoma in patients who received BFM-type first-line therapy, reinduction chemotherapy, followed by autologous SCT reported the following: [26][Level of evidence: 2A]

  2. Several additional studies suggest that allogeneic SCT may result in better outcome for refractory/relapsed anaplastic large cell lymphoma. [30] [31]

Vinblastine is active as a single agent in recurrent/refractory anaplastic large cell lymphoma; it induced complete remission (CR) in 25 of 30 evaluable patients (83%) in one study. [29] Nine of 25 patients treated with vinblastine alone remained in CR, with median follow-up of 7 years since the end of treatment. [29][Level of evidence: 3iiiA]

Crizotinib, a kinase inhibitor that blocks the activity of the NPM-ALK fusion protein, has been evaluated in children and adults with relapsed/refractory anaplastic large cell lymphoma. [32] Seven of nine children with anaplastic large cell lymphoma treated on the pediatric phase I study of crizotinib achieved complete responses. [33]

Brentuximab vedotin has been evaluated in adults with anaplastic large cell lymphoma. A phase II study of adults and adolescents with CD30-positive cancers that administered a dose of 1.8 mg/kg of brentuximab vedotin showed CR rates of approximately 55% to 60% and partial remission rates of 29%. [34]

Treatment Options Under Clinical Evaluation for Anaplastic Large Cell Lymphoma

Treatment options under clinical evaluation for anaplastic large cell lymphoma include the following:

Information about ongoing clinical trials is available from the NCI website.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I childhood anaplastic large cell lymphoma, stage II childhood anaplastic large cell lymphoma, stage III childhood anaplastic large cell lymphoma, stage IV childhood anaplastic large cell lymphoma and recurrent 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. 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.
  2. 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.
  3. Duyster J, Bai RY, Morris SW: Translocations involving anaplastic lymphoma kinase (ALK). Oncogene 20 (40): 5623-37, 2001.
  4. 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.
  5. Vose J, Armitage J, Weisenburger D, et al.: International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 26 (25): 4124-30, 2008.
  6. Stein H, Foss HD, Dürkop H, et al.: CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood 96 (12): 3681-95, 2000.
  7. Lamant L, McCarthy K, d'Amore E, et al.: Prognostic impact of morphologic and phenotypic features of childhood ALK-positive anaplastic large-cell lymphoma: results of the ALCL99 study. J Clin Oncol 29 (35): 4669-76, 2011.
  8. Alexander S, Kraveka JM, Weitzman S, et al.: Advanced stage anaplastic large cell lymphoma in children and adolescents: results of ANHL0131, a randomized phase III trial of APO versus a modified regimen with vinblastine: a report from the children's oncology group. Pediatr Blood Cancer 61 (12): 2236-42, 2014.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. Pillon M, Gregucci F, Lombardi A, et al.: Results of AIEOP LNH-97 protocol for the treatment of anaplastic large cell lymphoma of childhood. Pediatr Blood Cancer 59 (5): 828-33, 2012.
  18. 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.
  19. Brugières L, Le Deley MC, Rosolen A, et al.: Impact of the methotrexate administration dose on the need for intrathecal treatment in children and adolescents with anaplastic large-cell lymphoma: results of a randomized trial of the EICNHL Group. J Clin Oncol 27 (6): 897-903, 2009.
  20. Attarbaschi A, Mann G, Rosolen A, et al.: Limited stage I disease is not necessarily indicative of an excellent prognosis in childhood anaplastic large cell lymphoma. Blood 117 (21): 5616-9, 2011.
  21. Wrobel G, Mauguen A, Rosolen A, et al.: Safety assessment of intensive induction therapy in childhood anaplastic large cell lymphoma: report of the ALCL99 randomised trial. Pediatr Blood Cancer 56 (7): 1071-7, 2011.
  22. Le Deley MC, Rosolen A, Williams DM, et al.: Vinblastine in children and adolescents with high-risk anaplastic large-cell lymphoma: results of the randomized ALCL99-vinblastine trial. J Clin Oncol 28 (25): 3987-93, 2010.
  23. Williams D, Mori T, Reiter A, et al.: Central nervous system involvement in anaplastic large cell lymphoma in childhood: results from a multicentre European and Japanese study. Pediatr Blood Cancer 60 (10): E118-21, 2013.
  24. 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.
  25. Mori T, Takimoto T, Katano N, et al.: Recurrent childhood anaplastic large cell lymphoma: a retrospective analysis of registered cases in Japan. Br J Haematol 132 (5): 594-7, 2006.
  26. Woessmann W, Zimmermann M, Lenhard M, et al.: Relapsed or refractory anaplastic large-cell lymphoma in children and adolescents after Berlin-Frankfurt-Muenster (BFM)-type first-line therapy: a BFM-group study. J Clin Oncol 29 (22): 3065-71, 2011.
  27. 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.
  28. 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.
  29. Brugières L, Pacquement H, Le Deley MC, et al.: Single-drug vinblastine as salvage treatment for refractory or relapsed anaplastic large-cell lymphoma: a report from the French Society of Pediatric Oncology. J Clin Oncol 27 (30): 5056-61, 2009.
  30. Gross TG, Hale GA, He W, et al.: Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents. Biol Blood Marrow Transplant 16 (2): 223-30, 2010.
  31. 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.
  32. Gambacorti-Passerini C, Messa C, Pogliani EM: Crizotinib in anaplastic large-cell lymphoma. N Engl J Med 364 (8): 775-6, 2011.
  33. Mossé YP, Lim MS, Voss SD, et al.: Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study. Lancet Oncol 14 (6): 472-80, 2013.
  34. Pro B, Advani R, Brice P, et al.: Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol 30 (18): 2190-6, 2012.

Lymphoproliferative Disease Associated With Immunodeficiency in Children

Incidence

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 includes the following:

Clinical Presentation

Non-Hodgkin lymphoma (NHL) associated with immunodeficiency is usually aggressive, with most cases occurring in extralymphatic sites and a higher incidence of primary central nervous system (CNS) involvement. [1] [2] [3] [4]

Lymphoproliferative Disease Associated With Primary Immunodeficiency

Lymphoproliferative disease observed in primary immunodeficiency usually shows a mature B-cell phenotype and large cell histology. [2] Mature T-cell lymphoma and anaplastic large cell lymphoma have been observed. [2] Children with primary immunodeficiency and NHL are more likely to have high-stage disease and present with symptoms related to extranodal disease, particularly the gastrointestinal tract and CNS. [2]

Treatment options for lymphoproliferative disease associated with primary immunodeficiency

Treatment options for lymphoproliferative disease associated with primary immunodeficiency include the following:

  1. Chemotherapy.
  2. Allogeneic stem cell transplantation (SCT).

Patients with primary immunodeficiency can achieve complete and durable remissions with standard chemotherapy regimens for NHL, although toxicity is increased. [2] Recurrences in these patients are common and may not represent the same clonal disease. [5] Immunologic correction through allogeneic SCT is often required to prevent recurrences.

Patients with DNA repair defects (e.g., ataxia-telangiectasia) are particularly difficult to treat. [6] [7] Cytotoxic agents produce much more toxicity and greatly increase the risk of subsequent neoplasms in these patients. A Berlin-Frankfurt-Munster retrospective study showed the 10-year overall survival rate to be 58% in 38 children with ataxia telangiectasia or Nijmegen-breakage syndrome and acute lymphoblastic leukemia (n = 9), NHL (n = 28), and Hodgkin lymphoma (n = 1). Dosage-reduction of chemotherapeutic drugs was effective and reduced toxic side effects, but did not prevent subsequent neoplasms (10-year incidence, 25%). [8]

HIV-associated NHL

NHL in children with HIV often presents with fever, weight loss, and symptoms related to extranodal disease, such as abdominal pain or CNS symptoms. [1] Most childhood HIV-related NHL is of mature B-cell phenotype but with a spectrum, including primary effusion lymphoma, primary CNS lymphoma, mucosa-associated lymphoid tissue (MALT), Burkitt lymphoma/leukemia, and diffuse large B-cell lymphoma. [9] [10]

HIV-associated NHL can be broadly grouped into the following three subcategories:

  1. Systemic (nodal and extranodal). Approximately 80% of all NHL in HIV patients is considered to be systemic. [1]

  2. Primary CNS lymphoma.

  3. Body cavity–based lymphoma, also referred to as primary effusion lymphoma. Primary effusion lymphoma, 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. [11]

Highly active antiretroviral therapy has decreased the incidence of NHL in HIV-positive individuals, particularly for primary CNS lymphoma cases. [12] [13]

Treatment options for HIV-associated NHL

Treatment options for HIV-associated NHL include the following:

  1. Chemotherapy.

In the era of highly active antiretroviral therapy, children with HIV and NHL are treated with standard chemotherapy regimens for NHL, but careful attention to prophylaxis against and early detection of infection is warranted. [1] [12] [13] Treatment of recurrent disease is based on histology using standard approaches.

Posttransplant Lymphoproliferative Disease (PTLD)

Posttransplant lymphoproliferative disease (PTLD) represents a spectrum of clinically and morphologically heterogeneous lymphoid proliferations. Essentially all PTLD after HSCT is associated with EBV, but EBV-negative PTLD can be seen following solid organ transplant. [3] While most posttransplant lymphoproliferative diseases are of B-cell phenotype, approximately 10% are mature (peripheral) T-cell lymphomas. [4] The B-cell stimulation by EBV may result in multiple clones of proliferating B cells, and both polymorphic and monomorphic histologies may be present in a patient, even within the same lesion of PTLD. [14] Thus, histology of a single biopsied site may not be representative of the entire disease process.

The World Health Organization (WHO) has classified PTLD into the following three subtypes: [4]

EBV lymphoproliferative disease posttransplant may manifest as isolated hepatitis, lymphoid interstitial pneumonitis, meningoencephalitis, or an infectious mononucleosis-like syndrome. The definition of PTLD is frequently limited to lymphomatous lesions (low stage or high stage), which are often extranodal (frequently in the allograft). [3] Although less common, PTLD may present as a rapidly progressive, high-stage disease that clinically resembles septic shock, which has a poor prognosis; however, the use of rituximab and low-dose chemotherapy may improve the outcome. [15] [16]

Treatment options for PTLD

Treatment options for PTLD include the following:

  1. For localized resectable disease, surgical resection and, if possible, reduction of immunosuppressive therapy.

  2. Rituximab therapy alone. [17]

  3. Standard or slightly modified lymphoma-specific chemotherapy regimens for specific histology, with or without rituximab for B-cell PTLD. [18] [19] [20]

  4. For EBV-positive, B-cell PTLD, low-dose chemotherapy with or without rituximab. [16]; [21][Level of evidence: 3iiDiii]

First-line therapy for PTLD is to reduce immunosuppressive therapy as much as possible. [21] [22] However, this may not be possible because of the increased risk for organ rejection or graft-versus-host disease (GVHD).

Rituximab, an anti-CD20 antibody, has been used in the posttransplant setting. In a study of 144 children and adults who developed post-HSCT PTLD, it was reported that approximately 70% of patients who received rituximab survived. Survival was associated with reduction of immunosuppression as well, but older age, extranodal disease, and acute graft-versus-host disease were predictors of poor outcome. [17][Level of evidence: 3iiiA] Rituximab as a single agent to treat PTLD after organ transplant has demonstrated efficacy in adult patients, but data are lacking in pediatric patients.

Low-intensity chemotherapy has been effective in EBV-positive, CD20-positive B-lineage PTLD. [16] A Children's Oncology Group study using rituximab plus cyclophosphamide and prednisone in children with PTLD after solid organ transplantation in whom immune suppression was reduced demonstrated a 67% event-free survival. [16][Level of evidence: 2A] Other studies suggest that modified conventional lymphoma therapy is effective for PTLD with c-myc translocations and Burkitt histology. [19] [20][Level of evidence: 3iiDiii] Patients with T-cell or Hodgkin-like PTLD are usually treated with standard lymphoma-specific chemotherapy regimens. [23] [24] [25] [26]

Anti-rejection therapy is usually decreased or discontinued when chemotherapy is given to avoid excessive toxicity. There are no data to guide the re-initiation of immunosuppressive therapy after chemotherapy treatment. There is little evidence of benefit for chemotherapy following SCT.

Treatment options under clinical evaluation for PTLD

Treatment options under clinical evaluation for lymphoproliferative disease associated with PTLD include the following:

Information about ongoing clinical trials is available from the NCI website.

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. Loren AW, Porter DL, Stadtmauer EA, et al.: Post-transplant lymphoproliferative disorder: a review. Bone Marrow Transplant 31 (3): 145-55, 2003.
  4. Swerdlow SH, Webber SA, Chadburn A: Post-transplant lymphoproliferative disorders. 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 343-9.
  5. 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.
  6. Sandoval C, Swift M: Treatment of lymphoid malignancies in patients with ataxia-telangiectasia. Med Pediatr Oncol 31 (6): 491-7, 1998.
  7. Dembowska-Baginska B, Perek D, Brozyna A, et al.: Non-Hodgkin lymphoma (NHL) in children with Nijmegen Breakage syndrome (NBS). Pediatr Blood Cancer 52 (2): 186-90, 2009.
  8. Bienemann K, Burkhardt B, Modlich S, et al.: Promising therapy results for lymphoid malignancies in children with chromosomal breakage syndromes (Ataxia teleangiectasia or Nijmegen-breakage syndrome): a retrospective survey. Br J Haematol 155 (4): 468-76, 2011.
  9. 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.
  10. 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.
  11. Jaffe ES: Primary body cavity-based AIDS-related lymphomas. Evolution of a new disease entity. Am J Clin Pathol 105 (2): 141-3, 1996.
  12. 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.
  13. Godot C, Patte C, Blanche S, et al.: Characteristics and prognosis of B-cell lymphoma in HIV-infected children in the HAART era. J Pediatr Hematol Oncol 34 (7): e282-8, 2012.
  14. 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.
  15. Collins MH, Montone KT, Leahey AM, et al.: Autopsy pathology of pediatric posttransplant lymphoproliferative disorder. Pediatrics 107 (6): E89, 2001.
  16. Gross TG, Orjuela MA, Perkins SL, et al.: Low-dose chemotherapy and rituximab for posttransplant lymphoproliferative disease (PTLD): a Children's Oncology Group Report. Am J Transplant 12 (11): 3069-75, 2012.
  17. Styczynski J, Gil L, Tridello G, et al.: Response to rituximab-based therapy and risk factor analysis in Epstein Barr Virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Clin Infect Dis 57 (6): 794-802, 2013.
  18. 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.
  19. Picarsic J, Jaffe R, Mazariegos G, et al.: Post-transplant Burkitt lymphoma is a more aggressive and distinct form of post-transplant lymphoproliferative disorder. Cancer 117 (19): 4540-50, 2011.
  20. Windebank K, Walwyn T, Kirk R, et al.: Post cardiac transplantation lymphoproliferative disorder presenting as t(8;14) Burkitt leukaemia/lymphoma treated with low intensity chemotherapy and rituximab. Pediatr Blood Cancer 53 (3): 392-6, 2009.
  21. 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.
  22. 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.
  23. Yang F, Li Y, Braylan R, et al.: Pediatric T-cell post-transplant lymphoproliferative disorder after solid organ transplantation. Pediatr Blood Cancer 50 (2): 415-8, 2008.
  24. Williams KM, Higman MA, Chen AR, et al.: Successful treatment of a child with late-onset T-cell post-transplant lymphoproliferative disorder/lymphoma. Pediatr Blood Cancer 50 (3): 667-70, 2008.
  25. Dharnidharka VR, Douglas VK, Hunger SP, et al.: Hodgkin's lymphoma after post-transplant lymphoproliferative disease in a renal transplant recipient. Pediatr Transplant 8 (1): 87-90, 2004.
  26. Goyal RK, McEvoy L, Wilson DB: Hodgkin disease after renal transplantation in childhood. J Pediatr Hematol Oncol 18 (4): 392-5, 1996.
  27. 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.
  28. 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.
  29. Bollard CM, Gottschalk S, Torrano V, et al.: Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J Clin Oncol 32 (8): 798-808, 2014.

Rare NHL Occurring in Children

Low-grade or intermediate-grade mature B-cell lymphomas, such as small lymphocytic lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, mantle cell lymphoma, myeloma, or follicular cell lymphoma, are rarely seen in children. The most recent World Health Organization (WHO) classification has identified pediatric follicular lymphoma and pediatric nodal marginal zone lymphoma as entities separate from their adult counterparts. [1]

In an attempt to learn more about the clinical and pathologic features of these rare types of pediatric non-Hodgkin lymphoma (NHL), the Children's Oncology Group (COG) has opened a registry study (COG-ANHL04B1). This study banks tissue for pathobiology studies and collects limited data on clinical presentation and outcome of therapy.

Pediatric Follicular Lymphoma

Pediatric follicular lymphoma is a disease that genetically and clinically differs from its adult counterpart. The genetic hallmark of adult follicular lymphoma, the translocation of t(14;18)(q32;q21) involving BCL2, is typically not detectable in pediatric follicular lymphoma. [2] [3] [4] Molecular alterations observed in pediatric follicular lymphoma include translocations of the immunoglobulin locus and IRF4, losses of regions of chromosome 1p, and mutations of TNFSFR14 on chromosome 1p. [5] [6]

Pediatric follicular lymphoma predominantly occurs in males, is associated with a high proliferation rate, and is more likely to be localized disease. [7] In pediatric follicular lymphoma, a high-grade component (i.e., grade 3) resembling diffuse large B-cell lymphoma can frequently be detected at initial diagnosis but does not indicate a more aggressive clinical course in children. [2] [4] [8] Cervical lymph nodes and tonsils are common sites, but disease has also occurred in extranodal sites such as the testis, kidney, gastrointestinal tract, and parotid. [2] [3] [4] [8] [9] [10]

Treatment options for pediatric follicular lymphoma

Follicular lymphoma is rare in children, with only case reports and case series to guide therapy. The outcome of pediatric follicular lymphoma is excellent, with an event-free survival (EFS) of about 95%. [2] [4] [7] [8] [10] In contrast to adult follicular lymphoma, the clinical course is not dominated by relapses. [2] [4] [8] [9]

Treatment options for pediatric follicular lymphoma include the following:

  1. Surgery only.
  2. Multiagent chemotherapy.

For pediatric patients, it appears that BCL2 rearrangement negativity and a high proliferative index predict favorable disease. [2] In these patients, surgical resection with no further treatment is sufficient for completely resected, localized disease. For patients with BCL2-rearranged tumors, treatment similar to that of adult patients with follicular lymphoma is administered (refer to the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information).

One study suggested that for children with stage I disease who had a complete resection, a watch and wait approach without chemotherapy may be indicated. Patients with higher-stage disease also had a favorable outcome with low-intensity and intermediate-intensity chemotherapy, with 94% EFS and 100% overall survival (OS) with a 2-year median follow-up. [7]

MALT Lymphoma

Mucosa-associated lymphoid tissue (MALT) lymphomas observed in pediatric patients usually present as low-stage (stage I or stage II) disease and, rarely, can be associated with Helicobacter pylori (gastrointestinal) or chlamydial psittaci (conjunctival). [11] [12]

Treatment options for MALT lymphoma

Treatment options for MALT lymphoma include the following:

  1. Surgery only.
  2. Radiation therapy.
  3. Chemotherapy.

Most pediatric MALT lymphomas require no more than local therapy involving curative surgery and/or radiation therapy. [11]

Intralesional interferon-alpha for conjunctival MALT lymphoma has been described. [13]

Primary Central Nervous System (CNS) Lymphoma

Other types of NHL that may be rare in adults and are exceedingly rare in pediatric patients include primary CNS lymphoma. Because of small numbers of patients, it is difficult to ascertain whether the disease observed in children is the same as the disease observed in adults and determine optimal therapy.

Reports suggest that the outcome of pediatric patients with primary CNS lymphoma (OS, 70%–80%) may be superior to that of adults with primary CNS lymphoma. These reports suggest that long-term survival can be achieved without cranial irradiation. [14] [15] [16] [17]

Most children have diffuse large B-cell lymphoma, although other histologies can be observed.

Treatment options for primary CNS lymphoma

Treatment options for primary CNS lymphoma include the following:

  1. Chemotherapy.

Therapy with high-dose intravenous methotrexate and cytosine arabinoside is the most successful, and intrathecal chemotherapy may be needed only when malignant cells are present in the cerebrospinal fluid. [16]

There is a case report of repeated doses of rituximab, both intravenous and intraventricular, being administered to a 14-year-old boy with refractory primary CNS lymphoma, with an excellent result. [18] This apparently good outcome needs to be confirmed, and similar results have not been observed in adults. It is generally believed that rituximab does not cross the blood-brain barrier.

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

Peripheral T-cell Lymphoma

Peripheral T-cell lymphoma, excluding anaplastic large cell lymphoma, is rare in children.

Mature T-cell/natural killer (NK)-cell lymphoma or peripheral T-cell lymphoma has a postthymic phenotype (e.g., terminal deoxynucleotidyl transferase negative), usually expresses CD4 or CD8, and has rearrangement of T-cell receptor genes, either alpha-beta and/or gamma-delta chains. The most common phenotype observed in children is peripheral T-cell lymphoma–not otherwise specified, although angioimmunoblastic lymphoma, enteropathy-associated lymphoma (associated with celiac disease), subcutaneous panniculitis-like lymphoma, angiocentric lymphoma, and extranodal NK/T-cell peripheral T-cell lymphoma have been reported. [19] [20] [21]

A Japanese study described extranodal NK/T-cell lymphoma, nasal type as the most common peripheral T-cell lymphoma subtype among Japanese children (10 of 21 peripheral T-cell lymphoma cases). In adults, extranodal NK/T-cell lymphoma, nasal type is generally Epstein-Barr virus (EBV)-positive, and 60% of the cases observed in Japanese children were EBV-positive. [22]

Although very rare, gamma-delta hepatosplenic T-cell lymphoma may be seen in children. This tumor has also been associated with children and adolescents who have Crohn disease and have been treated with immunosuppressive therapy; this lymphoma has been fatal in all cases. [23]

Treatment options for peripheral T-cell lymphoma

Optimal therapy for peripheral T-cell lymphoma is unclear for both pediatric and adult patients.

Treatment options for peripheral T-cell lymphoma include the following:

  1. Chemotherapy.
  2. Radiation therapy.
  3. Allogeneic or autologous stem cell transplantation (SCT).

There have been three retrospective analyses of treatment and outcome for pediatric patients with peripheral T-cell lymphoma. The studies have reported the following:

Cutaneous T-cell Lymphoma

Primary cutaneous lymphomas are very rare in pediatric patients (1 case per 1 million person-years), but the incidence increases in adolescents and young adults. All histologies of NHL have been observed to involve the skin. Over 80% are of T-cell or NK-cell phenotype. [24]

There are very limited data on the best therapeutic approach to the treatment of primary cutaneous lymphoma in the pediatric population. Primary cutaneous anaplastic large cell lymphoma presents a particular problem. The diagnosis can be difficult to distinguish pathologically from more benign diseases such as lymphomatoid papulosis. [25] Primary cutaneous lymphomas are now thought to represent a spectrum of disorders, distinguished by clinical presentation.

Treatment options for cutaneous T-cell lymphoma

Because of the rarity of cutaneous T-cell lymphoma, no standard treatments have been established.

Primary cutaneous anaplastic large cell lymphoma usually does not express ALK and may be treated successfully with surgical resection and/or local radiation therapy without systemic chemotherapy. [26] There are reports of surgery alone also being curative for ALK-positive cutaneous anaplastic large cell lymphoma, but extensive staging and vigilant follow-up is required. [27] [28]

An oral retinoid (bexarotene) has been reported to be active against subcutaneous panniculitis-like T-cell lymphomas and cutaneous gamma-delta T-cell lymphomas in a series of 15 patients from three institutions. [29] In general, however, the optimal therapy for non–anaplastic large cell lymphoma peripheral T-cell lymphoma in childhood is unclear.

References:

  1. 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.
  2. Louissaint A Jr, Ackerman AM, Dias-Santagata D, et al.: Pediatric-type nodal follicular lymphoma: an indolent clonal proliferation in children and adults with high proliferation index and no BCL2 rearrangement. Blood 120 (12): 2395-404, 2012.
  3. Liu Q, Salaverria I, Pittaluga S, et al.: Follicular lymphomas in children and young adults: a comparison of the pediatric variant with usual follicular lymphoma. Am J Surg Pathol 37 (3): 333-43, 2013.
  4. Lorsbach RB, Shay-Seymore D, Moore J, et al.: Clinicopathologic analysis of follicular lymphoma occurring in children. Blood 99 (6): 1959-64, 2002.
  5. Salaverria I, Philipp C, Oschlies I, et al.: Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults. Blood 118 (1): 139-47, 2011.
  6. Launay E, Pangault C, Bertrand P, et al.: High rate of TNFRSF14 gene alterations related to 1p36 region in de novo follicular lymphoma and impact on prognosis. Leukemia 26 (3): 559-62, 2012.
  7. Attarbaschi A, Beishuizen A, Mann G, et al.: Children and adolescents with follicular lymphoma have an excellent prognosis with either limited chemotherapy or with a "Watch and wait" strategy after complete resection. Ann Hematol 92 (11): 1537-41, 2013.
  8. Oschlies I, Salaverria I, Mahn F, et al.: Pediatric follicular lymphoma--a clinico-pathological study of a population-based series of patients treated within the Non-Hodgkin's Lymphoma--Berlin-Frankfurt-Munster (NHL-BFM) multicenter trials. Haematologica 95 (2): 253-9, 2010.
  9. Lones MA, Raphael M, McCarthy K, et al.: Primary follicular lymphoma of the testis in children and adolescents. J Pediatr Hematol Oncol 34 (1): 68-71, 2012.
  10. Agrawal R, Wang J: Pediatric follicular lymphoma: a rare clinicopathologic entity. Arch Pathol Lab Med 133 (1): 142-6, 2009.
  11. 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.
  12. Stefanovic A, Lossos IS: Extranodal marginal zone lymphoma of the ocular adnexa. Blood 114 (3): 501-10, 2009.
  13. Holds J, Buchanan A, Hanson R: Intralesional interferon-α for the treatment of bilateral conjunctival mucosa-associated lymphoid tissue lymphoma. Pediatr Blood Cancer 59 (1): 176-8, 2012.
  14. 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.
  15. Shah AC, Kelly DR, Nabors LB, et al.: Treatment of primary CNS lymphoma with high-dose methotrexate in immunocompetent pediatric patients. Pediatr Blood Cancer 55 (6): 1227-30, 2010.
  16. Abla O, Weitzman S, Blay JY, et al.: Primary CNS lymphoma in children and adolescents: a descriptive analysis from the International Primary CNS Lymphoma Collaborative Group (IPCG). Clin Cancer Res 17 (2): 346-52, 2011.
  17. Yoon JH, Kang HJ, Kim H, et al.: Successful treatment of primary central nervous system lymphoma without irradiation in children: single center experience. J Korean Med Sci 27 (11): 1378-84, 2012.
  18. 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.
  19. 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.
  20. 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.
  21. Wang ZY, Li YX, Wang WH, et al.: Primary radiotherapy showed favorable outcome in treating extranodal nasal-type NK/T-cell lymphoma in children and adolescents. Blood 114 (23): 4771-6, 2009.
  22. Kobayashi R, Yamato K, Tanaka F, et al.: Retrospective analysis of non-anaplastic peripheral T-cell lymphoma in pediatric patients in Japan. Pediatr Blood Cancer 54 (2): 212-5, 2010.
  23. 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.
  24. Senerchia AA, Ribeiro KB, Rodriguez-Galindo C: Trends in incidence of primary cutaneous malignancies in children, adolescents, and young adults: a population-based study. Pediatr Blood Cancer 61 (2): 211-6, 2014.
  25. 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.
  26. Kempf W, Pfaltz K, Vermeer MH, et al.: EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Blood 118 (15): 4024-35, 2011.
  27. 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.
  28. Oschlies I, Lisfeld J, Lamant L, et al.: ALK-positive anaplastic large cell lymphoma limited to the skin: clinical, histopathological and molecular analysis of 6 pediatric cases. A report from the ALCL99 study. Haematologica 98 (1): 50-6, 2013.
  29. Mehta N, Wayne AS, Kim YH, et al.: Bexarotene is active against subcutaneous panniculitis-like T-cell lymphoma in adult and pediatric populations. Clin Lymphoma Myeloma Leuk 12 (1): 20-5, 2012.

Changes to This Summary (05/27/2015)

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.

This summary was reformatted.

This summary was comprehensively reviewed and extensively revised.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood non-Hodgkin lymphoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Non-Hodgkin Lymphoma Treatment are:

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Childhood Non-Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/types/lymphoma/hp/child-nhl-treatment-pdq. Accessed <MM/DD/YYYY>.

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