Because children and adolescents with Hodgkin lymphoma have excellent responses to frontline therapy, second-line (salvage) therapy has only been evaluated in a limited capacity. Because primary therapy fails in relatively few patients, no uniform second-line treatment strategy exists for this population.[1]
Adverse prognostic factors after relapse include the following:[2][Level of evidence C1]
- The presence of B symptoms (fever, weight loss, and night sweats) and extranodal disease.[3]
- Early relapse (occurring 3–12 months from the end of therapy).[4,5]
- Inadequate response to initial second-line therapy.[5]
Children with localized favorable relapses (≥12 months after completing therapy) whose original therapy involved reduced cycles of risk-adapted chemotherapy alone or chemotherapy with low-dose small-volume radiation therapy (consolidation therapy) have a high likelihood of achieving long-term survival after treatment with more intensive conventional chemotherapy.[6,7]
Treatment options for children and adolescents with refractory or recurrent Hodgkin lymphoma include the following:
Chemotherapy and Targeted Therapy
Chemotherapy is the recommended second-line therapy. The choice of specific agents, dose intensity, and number of cycles is 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 or recurrent pediatric Hodgkin lymphoma include the following:
Checkpoint Inhibitor Therapy
Treatments that block the interaction between programmed death-1 (PD-1) and its ligands have shown high levels of activity in adults with Hodgkin lymphoma.
Evidence (nivolumab):
- The anti–PD-1 antibody nivolumab induced objective responses in 20 of 23 adult patients (87%) with relapsed Hodgkin lymphoma.[30]
- In a phase I/II study of nivolumab in children with refractory malignancies, single-agent nivolumab was tolerable and showed antitumor activity.[31][Level of evidence C3]
- Among ten children with Hodgkin lymphoma, there was one complete response, two partial responses, and five cases of stable disease.
- In a phase II study, pediatric and young adult patients (70% were younger than 18 years) with relapsed or refractory Hodgkin lymphoma were treated with nivolumab and brentuximab vedotin.[32]
- After four induction cycles of nivolumab plus brentuximab vedotin, 59% of patients (23 of 43) achieved a complete metabolic response.
- Patients without a complete metabolic response also received intensification therapy with brentuximab vedotin and bendamustine before undergoing autologous HSCT. After intensification therapy and before consolidation therapy, 94% of patients achieved a complete metabolic response.
Nivolumab is FDA approved in adult patients with classical Hodgkin lymphoma who have relapsed or progressed after autologous HSCT and brentuximab vedotin or three or more lines of systemic therapy that included autologous HSCT.[30,33]
Evidence (pembrolizumab):
- The anti–PD-1 antibody pembrolizumab produced an objective response rate of 65% in 31 heavily pretreated adult patients with Hodgkin lymphoma who relapsed after receiving brentuximab vedotin.[34] For more information, see the Treatment of Recurrent Classic HL section in Hodgkin Lymphoma Treatment.
- A phase II study of 210 adult patients (median age, 35 years; range, 18–76 years) with refractory/relapsed classical Hodgkin lymphoma who were treated with pembrolizumab reported the following:[35][Level of evidence C3]
- An overall response rate of 69% (95% CI, 62.3%–75.2%), with a complete response rate of 22.4% (95% CI, 6.9%–28.6%).
- In a multicenter, nonrandomized, open-label, single-arm phase I/II study, 15 pediatric patients with relapsed or refractory Hodgkin lymphoma were treated with pembrolizumab at a dose of 2 mg/kg every 3 weeks.[36][Level of evidence C1]
- Two patients achieved complete responses, and seven patients achieved partial responses, for an overall objective response rate of 60% (95% CI, 32.2%–83.7%).
- Adverse events were documented in 97% of the 154 patients enrolled on the study; most were grades 1 to 2 toxicities.
- Grades 3 to 5 events, seen in 45% of the cases, consisted mostly of anemia and lymphopenia.
- Treatment interruptions were most commonly caused by transaminitis, hypertension, pleural effusion, and pneumonitis.
- Two deaths were attributed to drug administration (one resulting from pulmonary edema and the other from pleural effusion and pneumonitis).
Pembrolizumab is FDA approved for use in cases of refractory disease or relapse after three or more lines of therapy.
There are ongoing trials to determine the toxicity and efficacy of combining and/or comparing brentuximab vedotin and nivolumab with chemotherapy in pediatric patients with Hodgkin lymphoma.
Chemotherapy Followed by Autologous Hematopoietic Stem Cell Transplant (HSCT)
Myeloablative chemotherapy with autologous HSCT is the recommended approach for patients who develop refractory disease during therapy or relapsed disease within 1 year after completing therapy.[8,37-39]; [40,41][Level of evidence C1] This approach is also recommended for patients who have recurrent, extensive disease after the first year of completing therapy or for those with recurrent disease after initial therapy that included intensive (alkylating agents and anthracyclines) multiagent chemotherapy and radiation therapy.
- Autologous HSCT has been preferred for patients with relapsed Hodgkin lymphoma because of the historically high transplant-related mortality (TRM) associated with allogeneic transplant.[42] After autologous HSCT, the projected survival rate is 45% to 70%, and the PFS rate is 30% to 89%.[24,40,43,44]; [45,46][Level of evidence C1]
- Brentuximab vedotin as maintenance therapy, given for 1 year after autologous HSCT in adult patients with high risk of relapse or progression, was demonstrated to improve PFS in a randomized, placebo-controlled, phase III trial.[47]
- A multicenter, open-label, dose-escalation, phase I/II study evaluated the safety, maximum tolerated dose, and pharmacokinetics of brentuximab vedotin and identified a recommended phase II dose in 36 pediatric patients with relapsed or refractory classical Hodgkin lymphoma (n = 19) and anaplastic large cell lymphoma (n = 17). Toxicity was manageable (33% of patients had transient, limited-severity peripheral neuropathy), the maximum tolerated dose was not reached, and pediatric pharmacokinetics were similar to that of adults. The recommended phase II dose of brentuximab vedotin, 1.8 mg/m2, was administered for up to 16 cycles (median, 10 cycles) on the phase II arm. Among Hodgkin lymphoma participants on the phase II arm, 47% of patients achieved an overall response (33% complete response, 13% partial response), which provided a bridge to HSCT for some patients.[48][Level of evidence C1]
- The most commonly used preparative regimen for peripheral blood stem cell transplant is the BEAM regimen (carmustine [BCNU], etoposide, cytarabine, melphalan) or CBV regimen (cyclophosphamide, carmustine, etoposide).[38,43,44,46]; [40,41][Level of evidence C1] Carmustine may produce significant pulmonary toxicity.[46]
- Other noncarmustine-containing preparative regimens have been used, including high-dose busulfan, etoposide, and cyclophosphamide [49] and lomustine, cytarabine, cyclophosphamide, and etoposide (LACE).[50][Level of evidence C1]
Adverse prognostic features for outcome after autologous HSCT include extranodal disease at relapse, bulky mediastinal mass at time of transplant, advanced stage at relapse, primary refractory disease, poor response to chemotherapy, and a positive positron emission tomography scan before autologous HSCT.[2,43,44,46,51,52]
For more information about transplant, see Pediatric Autologous Hematopoietic Stem Cell Transplant and Pediatric Hematopoietic Stem Cell Transplant and Cellular Therapy for Cancer.
Involved-site Radiation Therapy (ISRT)
ISRT to sites of recurrent disease may enhance local control if these sites have not been previously irradiated. ISRT is generally administered after high-dose chemotherapy and stem cell rescue.[58] For patients who are not responsive to salvage therapy, ISRT may be an appropriate consideration before HSCT.[59,60] Consolidative ISRT is particularly appropriate in the following situations:[1]
- Low-risk patients whose positron emission tomography (PET) scans are negative after standard-dose salvage chemotherapy.
- Select standard-risk and/or high-risk patients who are treated with high-dose chemotherapy and HSCT.
Response Rates for Primary Refractory Hodgkin Lymphoma
Salvage rates for patients with primary refractory Hodgkin lymphoma are poor even with autologous HSCT and radiation. However, some studies have reported that intensification of therapy followed by HSCT consolidation can achieve long-term survival.
Evidence (response to treatment of primary refractory Hodgkin lymphoma):
- In one large series, the 5-year OS rate after primary refractory Hodgkin lymphoma was attained with aggressive second-line therapy (high-dose chemoradiation therapy) and autologous HSCT in 49% of patients.[61]
- 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.[4]
- A study of 53 adolescent patients like those who participated in the GPOH study had similar results for EFS and OS.[62] Chemosensitivity to standard-dose, second-line chemotherapy predicted better survival (OS rate, 66%), and tumors that remained refractory to chemotherapy did poorly (OS rate, 17%).[63]
- Another group reported a PFS rate of 80% post-HSCT for chemosensitive patients, compared with 0% for those with chemoresistant disease.[40]
Second Relapse After Initial Treatment With Autologous HSCT
In a phase II study, patients (median age, 26.5 years) who had relapsed or refractory disease after autologous HSCT received brentuximab vedotin, with an objective response rate of 73% and a complete remission rate of 34%. Patients who achieved a complete remission (n = 34) had a 3-year PFS rate of 58% and a 3-year OS rate of 73%. Only 6 of 34 patients proceeded to allogeneic HSCT while in remission.[24][Level of evidence B4]
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
Anti-CD30 chimeric antigen receptor (CAR) T-cell therapy clinical trials
Preliminary data on CAR T cells targeting CD30 have been published. In a phase I/II trial of 41 adults with multiply relapsed or refractory Hodgkin lymphoma, CD30 CAR T cells were administered after lymphoreduction with either bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine.[64] Treated patients had a median of seven previous lines of therapy, including brentuximab, checkpoint inhibitors, and autologous and allogeneic HSCTs. The overall response rate was 72% for the 32 patients with active disease who received fludarabine-based lymphodepletion. For all evaluable patients, the 1-year PFS rate was 36%, and the OS rate was 94%. The CD30 CAR T-cell therapy was well tolerated.
A number of clinical trials of anti-CD30 CAR T-cell therapy for patients with relapsed Hodgkin lymphoma are listed on ClinicalTrials.gov. The following is an example of a national and/or institutional clinical trial that is currently enrolling patients younger than 18 years:
- RELY-30 (NCT02917083) (CD30 CAR T Cells With or Without Cyclophosphamide and Fludarabine in Treating Participants With Relapsed or Refractory CD30-Positive Lymphoma): Patients aged 12 years and older with relapsed or refractory Hodgkin lymphoma will receive CD30 CAR T-cell therapy after chemotherapy or autologous transplant in this phase I study.
Other clinical trials
The following is an example of other national and/or institutional clinical trials that are currently being conducted:
Anti–PD-1 antibodies being studied in children with Hodgkin lymphoma include the following:
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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