Childhood Non-Hodgkin Lymphoma Treatment (PDQ®) 7/8 –Health Professional Version - National Cancer Institute

Childhood Non-Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version - National Cancer Institute

Childhood Non-Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version

Lymphoproliferative Disease Associated With Immunodeficiency in Children

In This Section

• Incidence
• Clinical Presentation
• Lymphoproliferative Disease Associated With Primary Immunodeficiency
  • Treatment options for lymphoproliferative disease associated with primary immunodeficiency
• NHL Associated With DNA Repair Defect Syndromes
  • Treatment options for NHL associated with DNA repair defect syndromes
• HIV-associated NHL
  • Treatment options for HIV-associated NHL
• Posttransplant Lymphoproliferative Disease (PTLD)
  • Treatment options for PTLD
  • Treatment options under clinical evaluation for PTLD

Incidence

The incidence of lymphoproliferative disease or lymphoma is 100-fold higher in immunocompromised children than in the general population. The causes of such immune deficiencies include the following:

• A genetically inherited defect (primary immunodeficiency).
• Secondary to HIV infection.
• Iatrogenic after transplantation (solid organ transplantation or allogeneic hematopoietic stem cell transplantation [HSCT]). Epstein-Barr virus (EBV) is associated with most of these tumors, but some tumors are not associated with any infectious agent.

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.[1-4]

Lymphoproliferative Disease Associated With Primary Immunodeficiency

Lymphoproliferative disease observed in primary immunodeficiency usually shows an aggressive mature B-cell phenotype and large cell histology.[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 in 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 with or without rituximab.
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]; [5][Level of evidence: 3iiiA] Recurrences in these patients are common and may not represent the same clonal disease.[6] Immunologic correction through allogeneic SCT is often required to prevent recurrences.

NHL Associated With DNA Repair Defect Syndromes

The incidence of NHL is increased in patients with DNA repair syndromes, including ataxia-telangiectasia, Nijmegen breakage syndrome, and constitutional mismatch repair deficiency. Aggressive mature B-cell NHL accounts for the majority of NHL seen in patients with ataxia-telangiectasia (84%) and Nijmegen breakage syndrome (46%), and T-cell lymphoblastic lymphoma (81%) is observed in patients with constitutional mismatch repair deficiency.[5]

Treatment options for NHL associated with DNA repair defect syndromes

Patients with DNA repair defects are particularly difficult to treat.[7,8] Overall 5-year to 10-year survival is poor, at 40% to 60%.[5,9]

Treatment options for NHL associated with DNA repair defect syndromes include the following:

1. Chemotherapy.

Cytotoxic agents produce much more toxicity and greatly increase the risk of subsequent neoplasms in these patients. One review reported that dose reduction of chemotherapeutic drugs was effective and reduced toxic effects, but did not prevent subsequent neoplasms (10-year incidence, 25%).[9]

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.[10,11]

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 human herpesvirus 8 (HHV-8) or Kaposi sarcoma herpesvirus infection, is primarily observed in adults infected with HIV but has been reported in HIV-infected children.[12]

Highly active antiretroviral therapy has decreased the incidence of NHL in HIV-positive individuals, particularly for primary CNS lymphoma cases.[13,14]

Treatment options for HIV-associated NHL

Treatment options for HIV-associated NHL include the following:

1. Chemotherapy with or without rituximab.

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.[1,13,14] Although the number of pediatric patients with HIV-associated NHL is too small to perform meaningful clinical trials, studies of adult patients support the addition of rituximab to standard regimens.[15] Treatment of recurrent disease is based on histology using standard approaches.

Posttransplant Lymphoproliferative Disease (PTLD)

PTLD represents a spectrum of clinically and morphologically heterogeneous lymphoid proliferations. Essentially all PTLDs after HSCT are associated with EBV, but EBV-negative PTLD can be seen after solid organ transplant.[3] While most PTLDs are of B-cell phenotype, approximately 10% are mature (peripheral) T-cell lymphomas.[16] 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.[17] 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:[16]

• Early lesion: Early lesions show germinal center expansion, but tissue architecture remains normal.
• Polymorphic PTLD: Presence of infiltrating T cells, disruption of nodal architecture, and necrosis distinguish polymorphic PTLD from early lesions.
• Monomorphic PTLD: Histologies observed in the monomorphic subtype are similar to those observed in NHL, with diffuse large B-cell lymphoma being the most common histology, followed by Burkitt lymphoma/leukemia, and with myeloma, plasmacytoma, and Hodgkin-like PTLD occurring rarely. T-cell PTLD is seen in about 10% of PTLD cases, may be EBV positive or EBV negative, and is usually of the mature T-cell subtype.[16]

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] PTLD may less commonly 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.[18,19] U.S. transplant and cancer registries show that PTLD accounts for about 3% of all pediatric NHL diagnoses; and that 65% of PTLDs are diffuse large B-cell lymphoma histology, and 9% are Burkitt histology.[20]

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.[21]
3. Standard or slightly modified lymphoma-specific chemotherapy regimens for specific histology, with or without rituximab for B-cell PTLD.[22-24]
4. For EBV-positive, B-cell PTLD, low-dose chemotherapy with or without rituximab.[19]; [25][Level of evidence: 3iiDiii]

First-line therapy for PTLD is to reduce immunosuppressive therapy as much as possible.[25,26] However, this may not be possible because of the increased risk of organ rejection or graft-versus-host disease (GVHD).

Rituximab, an anti-CD20 antibody, has been used in the posttransplant setting. 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 also associated with reduction of immunosuppression, but older age, extranodal disease, and acute GVHD were predictors of poor outcome.[21][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. (Refer to the Posttransplantation Lymphoproliferative Disorder (PTLD) section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)

Low-intensity chemotherapy has been effective in EBV-positive, CD20-positive B-lineage PTLD.[19,27] An event-free survival of 67% was demonstrated in 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.[19][Level of evidence: 2A] Other studies suggest that modified conventional lymphoma therapy is effective for PTLD with MYC translocations and Burkitt histology.[23,24][Level of evidence: 3iiDiii] Patients with T-cell or Hodgkin-like PTLD are usually treated with standard lymphoma-specific chemotherapy regimens.[28-31]

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

Adoptive immunotherapy with either donor lymphocytes or ex vivo–generated EBV-specific cytotoxic T-cells have been effective in treating PTLD after blood or bone marrow transplant.[32,33] Although this approach has been demonstrated to be feasible in patients with PTLD after solid organ transplant, it has not been demonstrated to be as effective or practical.[34]

Treatment options under clinical evaluation for PTLD

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

• ANHL1522 (NCT02900976) (Rituximab and Latent Membrane Protein [LMP]–Specific T Cells in Treating Pediatric Solid Organ Recipients With EBV-Positive Cluster of Differentiation (CD) 20–Positive PTLD): This is a limited-institution study for newly diagnosed patients (aged <30 years) with a monomorphic or polymorphic PTLD who have undergone a solid organ transplant. All patients will receive three weekly doses of rituximab followed by a response assessment. Patients who have a complete response (CR) to rituximab will receive an additional three doses of rituximab. Patients who do not achieve a CR to three doses of rituximab will receive LMP-specific T cells. LMP-specific T cells will be supplied from a third-party LMP-specific T-cell bank.

References

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