Current Clinical Trials

Treatment failure in children and adolescents with Hodgkin lymphoma can be divided into three groups:

• Primary progressive disease.
• Relapse limited to the site(s) of initial involvement (in patients treated with chemotherapy alone).
• Other relapse.

The presence of B symptoms and extranodal disease at the time of relapse are adverse prognostic features.[1] In one study from the German Pediatric Oncology Group (GPOH), patients with an early relapse (defined as occurring between 3–12 months from the end of therapy) had a 10-year event-free survival (EFS) of 55% and a 5-year overall survival (OS) of 78%. Patients with a late relapse (defined as occurring more than 12 months from the end of therapy) had a 10-year EFS and OS of 86% and 90%, respectively.[2] In the GPOH and the former Children’s Cancer Group (CCG) Hodgkin lymphoma trials, most relapses occurred in patients who received chemotherapy alone as primary treatment, and most of the relapses were limited to sites of initial involvement.[3,4] Patients with favorable disease at diagnosis (i.e., stage IA or stage IIA; no bulk; no B symptoms), with relapse confined to an area of initial involvement after chemotherapy and no radiation, can generally be salvaged with further chemotherapy and low-dose involved-field radiation therapy (LD-IFRT). For some postpubertal patients, standard-dose radiation may be an option.[5] For patients who are initially treated for low-stage disease without dose-intensive therapy, the salvage rates without hematopoietic stem cell transplant are very high.[2] For all other patients, treatment of relapse/progression includes induction chemotherapy,[6-10] and high-dose chemotherapy with hematopoietic stem cell transplant (HSCT).[11-13] Overall outcome is better following the use of autologous versus allogeneic stem cells because of the increased mortality associated with allogeneic transplant.[14] Following autologous HSCT, the projected survival rate is 45% to 70% and progression-free survival (PFS) is 30% to 65%.[15] Adverse prognostic features for outcome after autologous HSCT include extranodal disease at relapse, mediastinal mass at time of transplant, advanced stage at relapse, primary refractory disease, and a positive PET scan prior to autologous HSCT.[15,16] For patients who fail following autologous HSCT or for patients who cannot mobilize sufficient numbers of autologous stem cells, allogeneic HSCT has been used with encouraging results.[14,17-19] Whether such patients should receive further irradiation to previously radiated sites of relapse remains unclear.

A number of chemotherapy drugs not generally used in the initial treatment of Hodgkin lymphoma have documented activity against recurrent Hodgkin lymphoma including:

• moderate- or high-dose cytarabine
• carboplatin/cisplatin
• ifosfamide
• etoposide
• vinorelbine
• gemcitabine
• vinblastine [20]

Combination regimens used in the treatment of progressive/recurrent Hodgkin lymphoma include:

• ICE (ifosfamide, carboplatin, and etoposide) [8]
• DECAL (dexamethasone, etoposide, cisplatin, cytarabine, and L-asparaginase) [7]  [Note: These are results from a combined Hodgkin and non-Hodgkin lymphoma study. For Hodgkin lymphoma, DECA is the combination regimen currently used.]
• Ifosfamide and vinorelbine [9]
• Vinorelbine/gemcitabine [21]
• IEP–ABVD–COPP (ifosfamide, etoposide, prednisone–doxorubicin, bleomycin, vinblastine, dacarbazine–cyclophosphamide, vincristine, procarbazine, prednisone) [2]
• APE (cytosine arabinoside, cisplatin, etoposide) [22]
• For patients with CD20-positive disease, rituximab can be given alone or in combination with the above chemotherapy.

The most commonly utilized preparative regimen for peripheral blood stem cell transplant is the BEAM regimen (carmustine [BCNU], etoposide, cytarabine, melphalan). Carmustine may produce significant pulmonary toxicity. Other noncarmustine-containing preparative regimens include thiotepa and etoposide, combined with either cyclophosphamide, carboplatin, or melphalan. Busulfan has also been utilized in certain preparative regimens.

LD-IFRT to sites of recurrent disease should be given if these sites have not been previously irradiated. LD-IFRT is generally administered after high-dose chemotherapy and stem cell rescue.[23] Patients treated with HSCT may experience relapse as late as 5 years after the procedure; they should be monitored for relapse as well as late treatment sequelae.

Salvage rates for patients with primary refractory Hodgkin lymphoma are poor even with peripheral blood stem cell transplant and radiation. In one large series of patients, however, salvage after primary refractory Hodgkin lymphoma was attained with aggressive second-line therapy (high-dose chemoradiotherapy) and autologous stem cell transplantation. The OS rate was 49% at 5 years.[24] In a 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 EFS and OS rates of 41% and 51%, respectively.[2] Chemosensitivity to standard dose second-line chemotherapy predicted for a better survival (66% OS), and those who remained refractory did poorly (17% OS).[25] Salvage rates for patients who relapse after chemotherapy and LD-IFRT are approximately 30% to 50%. The salvage rate will probably be higher for patients who relapse after chemotherapy alone, particularly if the relapse is confined to a site of initial disease involvement.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

References

1. 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]
   
   
2. 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]
   
   
3. 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]
   
   
4. 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]
   
   
5. Wirth A, Corry J, Laidlaw C, et al.: Salvage radiotherapy for Hodgkin's disease following chemotherapy failure. Int J Radiat Oncol Biol Phys 39 (3): 599-607, 1997.  [PUBMED Abstract]
   
   
6. 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]
   
   
7. 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]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
12. Jones RJ, Piantadosi S, Mann RB, et al.: High-dose cytotoxic therapy and bone marrow transplantation for relapsed Hodgkin's disease. J Clin Oncol 8 (3): 527-37, 1990.  [PUBMED Abstract]
    
    
13. 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]
    
    
14. 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]
    
    
15. 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]
    
    
16. 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]
    
    
17. 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]
    
    
18. 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]
    
    
19. 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]
    
    
20. Little R, Wittes RE, Longo DL, et al.: Vinblastine for recurrent Hodgkin's disease following autologous bone marrow transplant. J Clin Oncol 16 (2): 584-8, 1998.  [PUBMED Abstract]
    
    
21. Ozkaynak MF, Jayabose S: Gemcitabine and vinorelbine as a salvage regimen for relapse in Hodgkin lymphoma after autologous hematopoietic stem cell transplantation. Pediatr Hematol Oncol 21 (2): 107-13, 2004.  [PUBMED Abstract]
    
    
22. 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]
    
    
23. 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]
    
    
24. 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]
    
    
25. 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]
    
    

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