Treatment of Primary Refractory/Recurrent Hodgkin Lymphoma in Children and Adolescents
The excellent response to frontline therapy among children and adolescents with Hodgkin lymphoma limits opportunities to evaluate second-line (salvage) therapy. Because of the small number of patients that fail primary therapy, no uniform second-line treatment strategy exists for this patient population. Adverse prognostic factors after relapse include the following:[Level of evidence: 3iiA]
Children with localized favorable (relapse ≥12 months after completing therapy) disease recurrences whose original therapy involved reduced cycles of risk-adapted therapy or with chemotherapy alone and/or low-dose involved-field radiation therapy (LD-IRFT) consolidation have a high likelihood of achieving long-term survival following treatment with more intensive conventional chemotherapy.[5,6]
Key concepts in regard to treatment of refractory/recurrent Hodgkin lymphoma in children and adolescents are as follows:
- Chemotherapy: Chemotherapy is the recommended second-line therapy, with the choice of specific agents, dose-intensity, and number of cycles determined by the initial therapy, disease characteristics at progression/relapse, and response to second-line therapy.
Agents used alone or in combination regimens in the treatment of refractory/recurrent Hodgkin lymphoma include the following:
- ICE (ifosfamide, carboplatin, and etoposide).
- Ifosfamide and vinorelbine.
- Vinorelbine and gemcitabine.
- IEP/ABVD/COPP (ifosfamide, etoposide, prednisone/doxorubicin, bleomycin, vinblastine, dacarbazine/cyclophosphamide, vincristine, procarbazine, prednisone).
- APE (cytosine arabinoside, cisplatin, and etoposide).
- MIED (high-dose methotrexate, ifosfamide, etoposide, and dexamethasone).
- Rituximab (for patients with CD20-positive disease) alone or in combination with second-line chemotherapy.
- Brentuximab vedotin.
Brentuximab vedotin has been evaluated in adults with Hodgkin lymphoma. A phase I study in adults with CD30-positive lymphomas identified a recommended phase II dose of 1.8 mg/kg on an every 3-week schedule and showed an objective response rate of 50% (6 of 12 patients) at the recommended phase II dose.[Level of evidence: 2Div] A phase II trial in adults with Hodgkin lymphoma (N = 102) who relapsed after autologous stem cell transplantation showed a complete remission rate of 32% and a partial remission rate of 40%.[14,15] The number of pediatric patients treated with brentuximab vedotin is not sufficient to determine whether they respond differently than adult patients. There are ongoing trials to determine the toxicity and efficacy of combining brentuximab vedotin with chemotherapy.
- Chemotherapy followed by autologous hematopoietic cell transplantation (HCT): Myeloablative chemotherapy with autologous HCT is the recommended approach for patients who develop refractory disease during therapy or relapsed disease within 1 year after completing therapy.[16-18,7,8,19-21]; [Level of evidence: 3iiA]; [Level of evidence:3iiiA] (Refer to the Autologous HCT section of the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.) In addition, this approach is also recommended for those who recur with extensive disease after the first year of completing therapy or for those who recur after initial therapy that included intensive (alkylating agents and anthracyclines) multiagent chemotherapy and radiation therapy.
- Autologous HCT has been preferred for patients with relapsed Hodgkin lymphoma because of the historically high transplant-related mortality (TRM) associated with allogeneic transplantation. Following autologous HCT, the projected survival rate is 45% to 70% and progression-free survival (PFS) is 30% to 89%.[22,25,26]; [Level of evidence: 3iiiA]
- The most commonly utilized preparative regimen for peripheral blood stem cell transplant is the BEAM regimen (carmustine [BCNU], etoposide, cytarabine, melphalan) or CBV regimen (cyclophosphamide, carmustine, etoposide).[21,25-27]; [Level of evidence: 3iiA]; [Level of evidence:3iiiA]
- Carmustine may produce significant pulmonary toxicity.
- Other noncarmustine-containing preparative regimens have been utilized, including high-dose busulfan, etoposide, and cyclophosphamide.
- Adverse prognostic features for outcome after autologous HCT include extranodal disease at relapse, mediastinal mass at time of transplant, advanced stage at relapse, primary refractory disease, and a positive positron emission tomography scan prior to autologous HCT.[1,25-27,29]
- Chemotherapy followed by allogeneic HCT: For patients who fail following autologous HCT or for patients with chemoresistant disease, allogeneic HCT has been used with encouraging results.[24,30-32] Investigations of reduced-intensity allogeneic transplantation that typically use fludarabine or low-dose total body irradiation to provide a nontoxic immunosuppression have demonstrated acceptable rates of TRM.[33-36] (Refer to the Allogeneic HCT section of the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.)
- LD-IFRT: LD-IFRT to sites of recurrent disease may enhance local control if these sites have not been previously irradiated. LD-IFRT is generally administered after high-dose chemotherapy and stem cell rescue.
Patients treated with HCT may experience relapse as late as 5 years after the procedure; they should be monitored for relapse and late treatment sequelae.
Response Rates for Primary Refractory Hodgkin Lymphoma
Salvage rates for patients with primary refractory Hodgkin lymphoma are poor even with autologous HCT and radiation. However, intensification of therapy followed by HCT consolidation has been reported to achieve long-term survival in some studies.
- In one large series of patients, 5-year overall survival (OS) after primary refractory Hodgkin lymphoma was attained with aggressive second-line therapy (high-dose chemoradiotherapy) and autologous HCT in 49%.
- In a Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) study, patients with primary refractory Hodgkin lymphoma (progressive disease on therapy or relapse within 3 months from the end of therapy) had 10-year event-free survival (EFS) and OS rates of 41% and 51%, respectively.
- A study of 53 adolescent patients of the same types as those who participated in the GPOH study had similar results for EFS and OS. Chemosensitivity to standard-dose second-line chemotherapy predicted a better survival (66% OS), and those who remained refractory did poorly (17% OS).
- Another group has reported the PFS post-HCT for chemosensitive patients as 80% compared with 0% for those with chemoresistant disease.
Treatment Options Under Clinical Evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted or is under analysis. Information about ongoing clinical trials is available from the NCI Web site.
- AHOD1221 (NCT01780662) (Brentuximab Vedotin and Gemcitabine Hydrochloride in Treating Younger Patients With Relapsed or Refractory Hodgkin Lymphoma): Both brentuximab vedotin and gemcitabine are active as single agents against Hodgkin lymphoma.[13,15,20,41,42] The objectives of this phase I/II trial include the following:
- Determine the maximum tolerated doses of brentuximab vedotin and gemcitabine hydrochloride when given together to pediatric patients with relapsed or refractory Hodgkin lymphoma.
- Define the incidence of adverse events at the maximum tolerated doses of the two agents.
- Determine the objective response rate for the brentuximab vedotin and gemcitabine regimen.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent/refractory childhood 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.
- Metzger ML, Hudson MM, Krasin MJ, et al.: Initial response to salvage therapy determines prognosis in relapsed pediatric Hodgkin lymphoma patients. Cancer 116 (18): 4376-84, 2010. [PUBMED Abstract]
- Moskowitz CH, Nimer SD, Zelenetz AD, et al.: A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood 97 (3): 616-23, 2001. [PUBMED Abstract]
- Schellong G, Dörffel W, Claviez A, et al.: Salvage therapy of progressive and recurrent Hodgkin's disease: results from a multicenter study of the pediatric DAL/GPOH-HD study group. J Clin Oncol 23 (25): 6181-9, 2005. [PUBMED Abstract]
- Gorde-Grosjean S, Oberlin O, Leblanc T, et al.: Outcome of children and adolescents with recurrent/refractory classical Hodgkin lymphoma, a study from the Société Française de Lutte contre le Cancer des Enfants et des Adolescents (SFCE). Br J Haematol 158 (5): 649-56, 2012. [PUBMED Abstract]
- Nachman JB, Sposto R, Herzog P, et al.: Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. J Clin Oncol 20 (18): 3765-71, 2002. [PUBMED Abstract]
- Rühl U, Albrecht M, Dieckmann K, et al.: Response-adapted radiotherapy in the treatment of pediatric Hodgkin's disease: an interim report at 5 years of the German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys 51 (5): 1209-18, 2001. [PUBMED Abstract]
- Cairo MS, Shen V, Krailo MD, et al.: Prospective randomized trial between two doses of granulocyte colony-stimulating factor after ifosfamide, carboplatin, and etoposide in children with recurrent or refractory solid tumors: a children's cancer group report. J Pediatr Hematol Oncol 23 (1): 30-8, 2001. [PUBMED Abstract]
- Bonfante V, Viviani S, Santoro A, et al.: Ifosfamide and vinorelbine: an active regimen for patients with relapsed or refractory Hodgkin's disease. Br J Haematol 103 (2): 533-5, 1998. [PUBMED Abstract]
- Cole PD, Schwartz CL, Drachtman RA, et al.: Phase II study of weekly gemcitabine and vinorelbine for children with recurrent or refractory Hodgkin's disease: a children's oncology group report. J Clin Oncol 27 (9): 1456-61, 2009. [PUBMED Abstract]
- Wimmer RS, Chauvenet AR, London WB, et al.: APE chemotherapy for children with relapsed Hodgkin disease: a Pediatric Oncology Group trial. Pediatr Blood Cancer 46 (3): 320-4, 2006. [PUBMED Abstract]
- Sandlund JT, Pui CH, Mahmoud H, et al.: Efficacy of high-dose methotrexate, ifosfamide, etoposide and dexamethasone salvage therapy for recurrent or refractory childhood malignant lymphoma. Ann Oncol 22 (2): 468-71, 2011. [PUBMED Abstract]
- Schulz H, Rehwald U, Morschhauser F, et al.: Rituximab in relapsed lymphocyte-predominant Hodgkin lymphoma: long-term results of a phase 2 trial by the German Hodgkin Lymphoma Study Group (GHSG). Blood 111 (1): 109-11, 2008. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Sea: ADCETRIS (Brentuximab Vedotin): Prescribing Information. Bothell, Wa: Seattle Genetics, 2012. Available online. Last accessed April 04, 2014.
- Younes A, Gopal AK, Smith SE, et al.: Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol 30 (18): 2183-9, 2012. [PUBMED Abstract]
- Rancea M, Monsef I, von Tresckow B, et al.: High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma. Cochrane Database Syst Rev 6: CD009411, 2013. [PUBMED Abstract]
- Aparicio J, Segura A, Garcerá S, et al.: ESHAP is an active regimen for relapsing Hodgkin's disease. Ann Oncol 10 (5): 593-5, 1999. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Zinzani PL, Bendandi M, Stefoni V, et al.: Value of gemcitabine treatment in heavily pretreated Hodgkin's disease patients. Haematologica 85 (9): 926-9, 2000. [PUBMED Abstract]
- Santoro A, Bredenfeld H, Devizzi L, et al.: Gemcitabine in the treatment of refractory Hodgkin's disease: results of a multicenter phase II study. J Clin Oncol 18 (13): 2615-9, 2000. [PUBMED Abstract]
- Baker KS, Gordon BG, Gross TG, et al.: Autologous hematopoietic stem-cell transplantation for relapsed or refractory Hodgkin's disease in children and adolescents. J Clin Oncol 17 (3): 825-31, 1999. [PUBMED Abstract]
- Shafer JA, Heslop HE, Brenner MK, et al.: Outcome of hematopoietic stem cell transplant as salvage therapy for Hodgkin's lymphoma in adolescents and young adults at a single institution. Leuk Lymphoma 51 (4): 664-70, 2010. [PUBMED Abstract]
- Claviez A, Sureda A, Schmitz N: Haematopoietic SCT for children and adolescents with relapsed and refractory Hodgkin's lymphoma. Bone Marrow Transplant 42 (Suppl 2): S16-24, 2008. [PUBMED Abstract]
- Peniket AJ, Ruiz de Elvira MC, Taghipour G, et al.: An EBMT registry matched study of allogeneic stem cell transplants for lymphoma: allogeneic transplantation is associated with a lower relapse rate but a higher procedure-related mortality rate than autologous transplantation. Bone Marrow Transplant 31 (8): 667-78, 2003. [PUBMED Abstract]
- Lieskovsky YE, Donaldson SS, Torres MA, et al.: High-dose therapy and autologous hematopoietic stem-cell transplantation for recurrent or refractory pediatric Hodgkin's disease: results and prognostic indices. J Clin Oncol 22 (22): 4532-40, 2004. [PUBMED Abstract]
- Akhtar S, Abdelsalam M, El Weshi A, et al.: High-dose chemotherapy and autologous stem cell transplantation for Hodgkin's lymphoma in the kingdom of Saudi Arabia: King Faisal specialist hospital and research center experience. Bone Marrow Transplant 42 (Suppl 1): S37-S40, 2008. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Wadehra N, Farag S, Bolwell B, et al.: Long-term outcome of Hodgkin disease patients following high-dose busulfan, etoposide, cyclophosphamide, and autologous stem cell transplantation. Biol Blood Marrow Transplant 12 (12): 1343-9, 2006. [PUBMED Abstract]
- Jabbour E, Hosing C, Ayers G, et al.: Pretransplant positive positron emission tomography/gallium scans predict poor outcome in patients with recurrent/refractory Hodgkin lymphoma. Cancer 109 (12): 2481-9, 2007. [PUBMED Abstract]
- Cooney JP, Stiff PJ, Toor AA, et al.: BEAM allogeneic transplantation for patients with Hodgkin's disease who relapse after autologous transplantation is safe and effective. Biol Blood Marrow Transplant 9 (3): 177-82, 2003. [PUBMED Abstract]
- Claviez A, Klingebiel T, Beyer J, et al.: Allogeneic peripheral blood stem cell transplantation following fludarabine-based conditioning in six children with advanced Hodgkin's disease. Ann Hematol 83 (4): 237-41, 2004. [PUBMED Abstract]
- Sureda A, Schmitz N: Role of allogeneic stem cell transplantation in relapsed or refractory Hodgkin's disease. Ann Oncol 13 (Suppl 1): 128-32, 2002. [PUBMED Abstract]
- Carella AM, Cavaliere M, Lerma E, et al.: Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin's disease and non-Hodgkin's lymphoma. J Clin Oncol 18 (23): 3918-24, 2000. [PUBMED Abstract]
- Robinson SP, Goldstone AH, Mackinnon S, et al.: Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation. Blood 100 (13): 4310-6, 2002. [PUBMED Abstract]
- Devetten MP, Hari PN, Carreras J, et al.: Unrelated donor reduced-intensity allogeneic hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma. Biol Blood Marrow Transplant 15 (1): 109-17, 2009. [PUBMED Abstract]
- Robinson SP, Sureda A, Canals C, et al.: Reduced intensity conditioning allogeneic stem cell transplantation for Hodgkin's lymphoma: identification of prognostic factors predicting outcome. Haematologica 94 (2): 230-8, 2009. [PUBMED Abstract]
- Wadhwa P, Shina DC, Schenkein D, et al.: Should involved-field radiation therapy be used as an adjunct to lymphoma autotransplantation? Bone Marrow Transplant 29 (3): 183-9, 2002. [PUBMED Abstract]
- Morabito F, Stelitano C, Luminari S, et al.: The role of high-dose therapy and autologous stem cell transplantation in patients with primary refractory Hodgkin's lymphoma: a report from the Gruppo Italiano per lo Studio dei Linfomi (GISL). Bone Marrow Transplant 37 (3): 283-8, 2006. [PUBMED Abstract]
- Akhtar S, El Weshi A, Rahal M, et al.: High-dose chemotherapy and autologous stem cell transplant in adolescent patients with relapsed or refractory Hodgkin's lymphoma. Bone Marrow Transplant 45 (3): 476-82, 2010. [PUBMED Abstract]
- Moskowitz CH, Kewalramani T, Nimer SD, et al.: Effectiveness of high dose chemoradiotherapy and autologous stem cell transplantation for patients with biopsy-proven primary refractory Hodgkin's disease. Br J Haematol 124 (5): 645-52, 2004. [PUBMED Abstract]
- Fosså A, Santoro A, Hiddemann W, et al.: Gemcitabine as a single agent in the treatment of relapsed or refractory aggressive non-Hodgkin's lymphoma. J Clin Oncol 17 (12): 3786-92, 1999. [PUBMED Abstract]
- Gopal AK, Ramchandren R, O'Connor OA, et al.: Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation. Blood 120 (3): 560-8, 2012. [PUBMED Abstract]