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]
- The presence of B symptoms (fever, weight loss, and night sweats) and extranodal disease.
- Early relapse (occurring between 3–12 months from the end of therapy).[3,4]
- Inadequate response to initial second-line therapy.
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.
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.
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.References
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