Chemotherapy Followed by Autologous HSCT

The EuroNet-PHL-R1 study enrolled 118 patients in a prospective nonrandomized study to investigate whether presalvage risk factors and fluorine F 18-fludeoxyglucose (18F-FDG) positron emission tomography (PET) response to reinduction chemotherapy could help determine whether chemotherapy alone or chemotherapy with autologous HSCT was needed in pediatric patients with refractory/relapsed Hodgkin lymphoma. All patients were given two cycles of reinduction therapy consisting of ifosfamide, etoposide, prednisolone (IEP) and adriamycin, bleomycin, vinblastine, dacarbazine (ABVD), followed by consolidation with either radiation therapy alone in patients with low-risk disease or high-dose chemotherapy (HDC)/autologous HSCT, with or without radiation therapy for patients with high-risk disease. There were three risk groups:[42]Patients in the R1 subgroup were defined as low risk, were not studied with 18F-FDG PET, and proceeded to radiation therapy. Patients in the R3 subgroup were defined as high risk and all received HDC/HSCT. Patients in the R2 subgroup were defined as low or high risk based on 18F-FDG PET response. If the PET scan was negative with 50% tumor-volume reduction, the patient was defined as low risk and proceeded to radiation therapy. Those with an inadequate 18F-FDG PET response (Deauville score >3) received HDC/HSCT with radiation therapy.For all 118 patients, the 5-year PFS rate was 71.3%, and the OS rate was 82.7%. For the 41 patients in the low-risk group, the PFS rate was 89.7%, and the OS rate was 97.4%. For the 18 patients in the R2 low-risk group who received HDC/HSCT off protocol, the PFS rate was 88.9%, and the OS rate was 100%. For the 59 patients with high-risk disease, the PFS rate was 53.3%, and the OS rate was 66.5%.This trial showed that 18F-FDG PET response-guided therapy in pediatric patients with relapsed/refractory Hodgkin lymphoma can identify patients who may have excellent outcomes without undergoing HSCT.

The EuroNet-PHL-R1 study enrolled 118 patients in a prospective nonrandomized study to investigate whether presalvage risk factors and fluorine F 18-fludeoxyglucose (18F-FDG) positron emission tomography (PET) response to reinduction chemotherapy could help determine whether chemotherapy alone or chemotherapy with autologous HSCT was needed in pediatric patients with refractory/relapsed Hodgkin lymphoma. All patients were given two cycles of reinduction therapy consisting of ifosfamide, etoposide, prednisolone (IEP) and adriamycin, bleomycin, vinblastine, dacarbazine (ABVD), followed by consolidation with either radiation therapy alone in patients with low-risk disease or high-dose chemotherapy (HDC)/autologous HSCT, with or without radiation therapy for patients with high-risk disease. There were three risk groups:[42]Patients in the R1 subgroup were defined as low risk, were not studied with 18F-FDG PET, and proceeded to radiation therapy. Patients in the R3 subgroup were defined as high risk and all received HDC/HSCT. Patients in the R2 subgroup were defined as low or high risk based on 18F-FDG PET response. If the PET scan was negative with 50% tumor-volume reduction, the patient was defined as low risk and proceeded to radiation therapy. Those with an inadequate 18F-FDG PET response (Deauville score >3) received HDC/HSCT with radiation therapy.For all 118 patients, the 5-year PFS rate was 71.3%, and the OS rate was 82.7%. For the 41 patients in the low-risk group, the PFS rate was 89.7%, and the OS rate was 97.4%. For the 18 patients in the R2 low-risk group who received HDC/HSCT off protocol, the PFS rate was 88.9%, and the OS rate was 100%. For the 59 patients with high-risk disease, the PFS rate was 53.3%, and the OS rate was 66.5%.This trial showed that 18F-FDG PET response-guided therapy in pediatric patients with relapsed/refractory Hodgkin lymphoma can identify patients who may have excellent outcomes without undergoing HSCT.

R1: Patients with relapse longer than 12 months after completion of initial therapy, who had early-stage disease and received two cycles of chemotherapy.

The EuroNet-PHL-R1 study enrolled 118 patients in a prospective nonrandomized study to investigate whether presalvage risk factors and fluorine F 18-fludeoxyglucose (18F-FDG) positron emission tomography (PET) response to reinduction chemotherapy could help determine whether chemotherapy alone or chemotherapy with autologous HSCT was needed in pediatric patients with refractory/relapsed Hodgkin lymphoma. All patients were given two cycles of reinduction therapy consisting of ifosfamide, etoposide, prednisolone (IEP) and adriamycin, bleomycin, vinblastine, dacarbazine (ABVD), followed by consolidation with either radiation therapy alone in patients with low-risk disease or high-dose chemotherapy (HDC)/autologous HSCT, with or without radiation therapy for patients with high-risk disease. There were three risk groups:[42]Patients in the R1 subgroup were defined as low risk, were not studied with 18F-FDG PET, and proceeded to radiation therapy. Patients in the R3 subgroup were defined as high risk and all received HDC/HSCT. Patients in the R2 subgroup were defined as low or high risk based on 18F-FDG PET response. If the PET scan was negative with 50% tumor-volume reduction, the patient was defined as low risk and proceeded to radiation therapy. Those with an inadequate 18F-FDG PET response (Deauville score >3) received HDC/HSCT with radiation therapy.For all 118 patients, the 5-year PFS rate was 71.3%, and the OS rate was 82.7%. For the 41 patients in the low-risk group, the PFS rate was 89.7%, and the OS rate was 97.4%. For the 18 patients in the R2 low-risk group who received HDC/HSCT off protocol, the PFS rate was 88.9%, and the OS rate was 100%. For the 59 patients with high-risk disease, the PFS rate was 53.3%, and the OS rate was 66.5%.This trial showed that 18F-FDG PET response-guided therapy in pediatric patients with relapsed/refractory Hodgkin lymphoma can identify patients who may have excellent outcomes without undergoing HSCT.

R3: Patients with progression during or up to 3 months after completion of initial therapy.

The EuroNet-PHL-R1 study enrolled 118 patients in a prospective nonrandomized study to investigate whether presalvage risk factors and fluorine F 18-fludeoxyglucose (18F-FDG) positron emission tomography (PET) response to reinduction chemotherapy could help determine whether chemotherapy alone or chemotherapy with autologous HSCT was needed in pediatric patients with refractory/relapsed Hodgkin lymphoma. All patients were given two cycles of reinduction therapy consisting of ifosfamide, etoposide, prednisolone (IEP) and adriamycin, bleomycin, vinblastine, dacarbazine (ABVD), followed by consolidation with either radiation therapy alone in patients with low-risk disease or high-dose chemotherapy (HDC)/autologous HSCT, with or without radiation therapy for patients with high-risk disease. There were three risk groups:[42]Patients in the R1 subgroup were defined as low risk, were not studied with 18F-FDG PET, and proceeded to radiation therapy. Patients in the R3 subgroup were defined as high risk and all received HDC/HSCT. Patients in the R2 subgroup were defined as low or high risk based on 18F-FDG PET response. If the PET scan was negative with 50% tumor-volume reduction, the patient was defined as low risk and proceeded to radiation therapy. Those with an inadequate 18F-FDG PET response (Deauville score >3) received HDC/HSCT with radiation therapy.For all 118 patients, the 5-year PFS rate was 71.3%, and the OS rate was 82.7%. For the 41 patients in the low-risk group, the PFS rate was 89.7%, and the OS rate was 97.4%. For the 18 patients in the R2 low-risk group who received HDC/HSCT off protocol, the PFS rate was 88.9%, and the OS rate was 100%. For the 59 patients with high-risk disease, the PFS rate was 53.3%, and the OS rate was 66.5%.This trial showed that 18F-FDG PET response-guided therapy in pediatric patients with relapsed/refractory Hodgkin lymphoma can identify patients who may have excellent outcomes without undergoing HSCT.

R2: Patients with all other relapses.

Autologous HSCT has been preferred for patients with relapsed Hodgkin lymphoma because of the historically high transplant-related mortality (TRM) associated with allogeneic transplant.[43] After autologous HSCT, the projected survival rate is 45% to 70%, and the PFS rate is 30% to 89%.[23,40,44,45]; [46,47][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, demonstrated improved PFS in a randomized, placebo-controlled, phase III trial.[48]

Brentuximab vedotin as consolidation therapy (after autologous HSCT) was evaluated in 67 pediatric patients with relapsed or refractory Hodgkin lymphoma. The median follow-up was 37 months, and the 3-year PFS rate was 85%. About 69% of these patients (46 of 67) received brentuximab vedotin at any point during the pre-HSCT salvage treatment, for either upfront therapy or reinduction therapy.[49]

A multicenter, open-label, dose-escalation, phase I/II study evaluated the safety, maximum tolerated dose, and pharmacokinetics of brentuximab vedotin. The study 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) in the phase II arm. In this arm, 47% of Hodgkin lymphoma participants achieved an overall response (33% complete response, 13% partial response), which provided a bridge to HSCT for some patients.[50][Level of evidence C1]

The most commonly used preparative regimens for peripheral blood HSCT are either carmustine (BCNU), etoposide, cytarabine, melphalan (BEAM) or cyclophosphamide, carmustine, etoposide (CBV).[38,44,45,47]; [40,41][Level of evidence C1] Carmustine may produce significant pulmonary toxicity.[47]

Other noncarmustine-containing preparative regimens have been used, including high-dose busulfan, etoposide, and cyclophosphamide [51] and lomustine, cytarabine, cyclophosphamide, and etoposide (LACE).[52][Level of evidence C1]