Lymphoproliferative Disease Associated With Immunodeficiency in Children

Regardless of the etiology of the immune defect, immunodeficient children with lymphoma have a worse prognosis than does the general population with non-Hodgkin lymphoma (NHL).[1,2,3,4] One potential exception is the more indolent low-grade lymphomas (e.g., mucosa-associated lymphoid tissue [MALT] lymphomas), which have developed in patients with common variable immunodeficiency or other immunodeficient states.[5,6] If the disease is localized and amenable to complete surgical resection and/or radiation therapy, the outcome is quite favorable; however, most NHL in this population is high-stage (stage III or IV) and requires systemic cytotoxic therapy. These patients usually tolerate cytotoxic therapy poorly, with increased morbidity and mortality due to increased infectious complications and often increased end-organ toxicities. (Refer to the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information about MALT lymphomas.)

In the era of highly active antiretroviral therapy, children with human immunodeficiency virus and NHL should be treated with standard chemotherapy regimens for NHL, but careful attention to prophylaxis against and early detection of infection is warranted.[1,7] Patients with primary immunodeficiency can achieve complete and durable remissions with standard chemotherapy regimens for NHL, though again, toxicity is increased.[2] Recurrences in these patients are common and may not represent the same clonal disease.[8] Immunologic correction through allogeneic stem cell transplantation is often required to prevent recurrences. Patients with DNA repair defects (e.g., ataxia-telangiectasia) are particularly difficult to treat.[4,9] Cytotoxic agents produce much more toxicity and greatly increase the risk of secondary malignancies in these patients. Survival is rare at 5 years postdiagnosis.

In posttransplant lymphoproliferative disease (PTLD), first-line therapy is the reduction of immunosuppression, as can be tolerated.[3,10] Rituximab, an anti-CD20 antibody, has been used with some success, but data for its use in children are sparse. Rituximab plus low-intensity chemotherapy may also be effective, even in PTLDs with the t(8;14) Burkitt lymphoma marker.[11][Level of evidence: 3iiDiii] Patients with T-cell or Hodgkin-like PTLD are usually treated with standard lymphoma-specific chemotherapy regimens.[12,13,14,15]

Standard Treatment Options

• Standard chemotherapy regimens for specific histology.[1,2,8,16]
• Low-dose chemotherapy.[3,11][Level of evidence: 3iiDiii]

Treatment Options Under Clinical Evaluation

The following is an example of a national or international clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

• Adoptive immunotherapy with either donor lymphocytes or ex vivo –generated Epstein-Barr virus–specific cytotoxic T-cells have been effective in treating PTLD following blood or bone marrow transplant.[17,18] Though this approach has been demonstrated to be feasible in patients with PTLD following solid organ transplant, it has not been demonstrated to be as effective or practical.

References:

1. McClain KL, Joshi VV, Murphy SB: Cancers in children with HIV infection. Hematol Oncol Clin North Am 10 (5): 1189-201, 1996.
2. Seidemann K, Tiemann M, Henze G, et al.: Therapy for non-Hodgkin lymphoma in children with primary immunodeficiency: analysis of 19 patients from the BFM trials. Med Pediatr Oncol 33 (6): 536-44, 1999.
3. Gross TG, Bucuvalas JC, Park JR, et al.: Low-dose chemotherapy for Epstein-Barr virus-positive post-transplantation lymphoproliferative disease in children after solid organ transplantation. J Clin Oncol 23 (27): 6481-8, 2005.
4. 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.
5. Aghamohammadi A, Parvaneh N, Tirgari F, et al.: Lymphoma of mucosa-associated lymphoid tissue in common variable immunodeficiency. Leuk Lymphoma 47 (2): 343-6, 2006.
6. 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.
7. 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.
8. 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.
9. Sandoval C, Swift M: Treatment of lymphoid malignancies in patients with ataxia-telangiectasia. Med Pediatr Oncol 31 (6): 491-7, 1998.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. Goyal RK, McEvoy L, Wilson DB: Hodgkin disease after renal transplantation in childhood. J Pediatr Hematol Oncol 18 (4): 392-5, 1996.
16. 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.
17. 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.
18. 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.