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Childhood Non-Hodgkin Lymphoma Treatment (Professional) (cont.)

Recurrent Childhood NHL Treatment

Outcome for recurrent non-Hodgkin lymphoma (NHL) in children and adolescents depends on histologic subtype. A Children's Cancer Group study (CCG-5912) was able to achieve complete remission (CR) in 40% of NHL patients.[1] A Pediatric Oncology Group study showed a 70% response rate and 40% CR rate.[2] Radiation therapy may have a role in treating patients who have not had a complete response to chemotherapy. All patients with primary refractory or relapsed NHL should be considered for clinical trials.

For recurrent or refractory B-lineage NHL, survival is generally 10% to 20%.[3,4,5,6,7] Chemoresistance is a major problem, making remission difficult to achieve. There is no standard treatment option for patients with recurrent or progressive disease. The use of single-agent rituximab, as well as rituximab combined with standard cytotoxic chemotherapy, has shown activity in the treatment of B-cell lymphoma patients.[8][Level of evidence: 3iiiDii] A Children's Oncology Group (COG) study using rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) to treat relapsed/refractory B-cell NHL (diffuse large B-cell lymphoma and Burkitt lymphoma) showed a CR/partial remission (PR) rate of 60%.[9][Level of evidence: 3iiA] If remission can be achieved, high-dose therapy and stem cell transplantation (SCT) may be pursued. The benefit of autologous versus allogeneic SCT is unclear.[5,10,11,12]; [13][Level of evidence: 2A]; [14][Level of evidence: 3iiiDii] (Refer to the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation). An analysis of the Center for International Blood and Marrow Transplant Research (CIBMTR) data demonstrated no difference using either autologous or allogeneic donor stem cell sources, with 2-year event-free survival (EFS) to be 30% for diffuse large B-cell lymphoma and 50% for Burkitt lymphoma. This analysis also showed patients not in remission at time of transplant do significantly worse.[12,13] For patients who have a second relapse after initial autologous SCT, an allogeneic SCT was found to be a promising treatment in a study of adults with diffuse large B-cell lymphoma.[15]

For recurrent or refractory lymphoblastic lymphoma, survival in the literature ranges from 10% to 40%.[5,16]; [17,18][Level of evidence: 3iiiA] As with Burkitt lymphoma, chemoresistant disease is common. There is no standard treatment option for patients with recurrent or progressive disease. A COG phase II study of nelarabine (compound 506U78) as a single agent demonstrated a response rate of 40%.[19] The CIBMTR analysis demonstrated that EFS was significantly worse using autologous (4%) versus allogeneic (40%) donor stem cell source, with all failures resulting from progressive disease.[12]

For recurrent or refractory anaplastic large cell lymphoma, 40% to 60% of patients can achieve long-term survival.[5,20,21] There is no standard approach for recurrent/refractory anaplastic large cell lymphoma; standard chemotherapy, followed by autologous SCT or allogeneic SCT, if remission can be achieved, have all been employed in this setting.[5,12,20,21]; [13][Level of evidence: 2A] In a retrospective study of relapsed or refractory anaplastic large cell lymphoma in patients who received Berlin-Frankfurt-Muenster–type first-line therapy, reinduction chemotherapy followed by autologous stem cell transplant resulted in 59% 5-year EFS and 77% overall survival.[21][Level of evidence: 2A] However, outcome of patients with bone marrow or central nervous system involvement, relapse during first-line therapy, or CD3-positive anaplastic large cell lymphoma was poor. These patients may benefit from allogeneic transplantation.[21] Several additional studies suggest that allogeneic SCT may result in better outcome for refractory/relapsed anaplastic large cell lymphoma.[12,22] Vinblastine is active as a single agent in recurrent/refractory anaplastic large cell lymphoma, inducing CR in 25 (83%) of 30 evaluable patients in one study.[23] Nine of 25 patients treated with vinblastine alone remained in CR with median follow-up of 7 years since the end of treatment.[23][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.[24,25] There are two case reports of adults with anaplastic large cell lymphoma who achieved complete responses to crizotinib, and seven of eight children with anaplastic large cell lymphoma treated on the pediatric phase I study of crizotinib achieved complete responses.[24,25]

Brentuximab vedotin has been evaluated in adults with anaplastic large cell lymphoma. A phase I study in adults with CD30-positive cancers identified a recommended phase II dose of 1.8 mg/kg, administered every 3 weeks; two of two patients with anaplastic large cell lymphoma achieved CR.[26] A phase II trial in adults with relapsed anaplastic large cell lymphoma has shown CR rates of approximately 55% to 60% and PR rates of 29%.[27] The number of pediatric patients treated with brentuximab vedotin is not sufficient to determine whether they respond differently than adult patients.

Treatment Options

Burkitt lymphoma and diffuse large B-cell lymphoma

  • DECAL: dexamethasone, etoposide, cisplatin, cytarabine, and L-asparaginase.[1]
  • ICE (ifosfamide, carboplatin, and etoposide) plus rituximab (for B-cell lymphoma).[9]
  • Allogeneic or autologous bone marrow transplantation (BMT).[12]

Lymphoblastic lymphoma

  • DECAL: dexamethasone, etoposide, cisplatin, cytarabine, and L-asparaginase.[1]
  • ICE: ifosfamide, carboplatin, and etoposide.[2]
  • Allogeneic BMT.[12]

Anaplastic large cell lymphoma

  • DECAL: dexamethasone, etoposide, cisplatin, cytarabine, and L-asparaginase.[1]
  • ICE: ifosfamide, carboplatin, and etoposide.[2]
  • Vinblastine (for anaplastic large cell lymphoma).[23]
  • Allogeneic or autologous BMT.[12]

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.

  • COG-ADVL0912 (Crizotinib in Treating Young Patients With Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma): The ALK inhibitor, crizotinib, is under phase I evaluation in children. The study has a stratum for children with ALK and anaplastic large cell lymphoma.
  • COG-ADVL1114 (Temsirolimus, Dexamethasone, Mitoxantrone Hydrochloride, Vincristine Sulfate, and Pegaspargase in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia [ALL] or NHL): This is a phase I trial to determine the feasibility and safety of adding three doses of temsirolimus (intravenously) to the United Kingdom ALLR3 induction regimen for patients with relapsed ALL and NHL.

Current Clinical Trials

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

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


  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. Attias D, Weitzman S: The efficacy of rituximab in high-grade pediatric B-cell lymphoma/leukemia: a review of available evidence. Curr Opin Pediatr 20 (1): 17-22, 2008.
  9. 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.
  10. Ladenstein R, Pearce R, Hartmann O, et al.: High-dose chemotherapy with autologous bone marrow rescue in children with poor-risk Burkitt's lymphoma: a report from the European Lymphoma Bone Marrow Transplantation Registry. Blood 90 (8): 2921-30, 1997.
  11. Sandlund JT, Bowman L, Heslop HE, et al.: Intensive chemotherapy with hematopoietic stem-cell support for children with recurrent or refractory NHL. Cytotherapy 4 (3): 253-8, 2002.
  12. 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.
  13. 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.
  14. 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.
  15. van Kampen RJ, Canals C, Schouten HC, et al.: Allogeneic stem-cell transplantation as salvage therapy for patients with diffuse large B-cell non-Hodgkin's lymphoma relapsing after an autologous stem-cell transplantation: an analysis of the European Group for Blood and Marrow Transplantation Registry. J Clin Oncol 29 (10): 1342-8, 2011.
  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. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. Gambacorti-Passerini C, Messa C, Pogliani EM: Crizotinib in anaplastic large-cell lymphoma. N Engl J Med 364 (8): 775-6, 2011.
  25. Mosse YP, Balis FM, Lim MS, et al.: Efficacy of crizotinib in children with relapsed/refractory ALK-driven tumors including anaplastic large cell lymphoma and neuroblastoma: a Children's Oncology Group phase I consortium study. [Abstract] J Clin Oncol 30 (Suppl 15): A-9500, 2012.
  26. Younes A, Bartlett NL, Leonard JP, et al.: Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363 (19): 1812-21, 2010.
  27. 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.
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