This topic addresses the management of recurrent Hodgkin lymphoma. While autologous stem cell transplantation may be appropriate for select cases of recurrent disease following comprehensive combined-modality therapy, other options exist for patients treated with lower-dose therapy for early-stage disease. Additionally, innovative targeted therapies provide newer salvage options to consider. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. By combining the most recent medical literature and expert opinion, this revised guideline can aid clinicians in the complex decision-making associated with the management of recurrent Hodgkin lymphoma.
Summary of Literature Review
Classical Hodgkin lymphoma is a highly curable cancer, even in advanced stages. Although radiation therapy (RT) alone improved disease-free survival (DFS) for many years, the management of classical Hodgkin lymphoma has changed dramatically over the past 2 decades with the use of highly effective systemic therapies and the subsequent reduction in the use of radiation. Even with combined-modality therapy (CMT), rates of relapse can vary from 5% for early-stage disease to 35% for more advanced stages.[2,3] Approximately 10% of patients will have disease that is refractory to initial therapy. Even in the setting of relapsed or refractory disease, classical Hodgkin lymphoma remains salvageable. The standard of care for relapsed/refractory disease is either conventional chemotherapy or high-dose chemotherapy with autologous stem cell transplantation (HDCT + ASCT). The role of RT in relapsed/refractory disease remains controversial and is reviewed in these guidelines.
Definitions and Determination of Relapsed/Refractory Disease
Relapse or recurrence can be defined as the reappearance of disease after initial therapy and complete response (CR) in the site of prior disease and/or in new sites. Progression refers to evidence of increasing disease after achievement of stable disease, partial remission (PR), or CR, whereas refractory disease is a failure to achieve either a CR or PR and may represent a more significant degree of radiation or drug resistance.[5,6]
Current National Comprehensive Cancer Network guidelines recommend biopsy to document relapse, progression, or refractory disease. Until recently, guidelines as to how to document progression of disease in the setting of incomplete remission remained unclear. Therefore, it is uncertain whether in practice biopsies are routinely performed according to this standard. However, biologic confirmation of disease is recommended. A biopsy may also be warranted in patients whose disease is refractory to therapy to confirm the initial diagnosis of classical Hodgkin lymphoma.
The majority of relapses following a CR in patients treated for classical Hodgkin lymphoma occur within 3 years of therapy, so routine surveillance by clinical examination is an essential component of a survivorship plan (see the ACR Appropriateness Criteria® Follow-up of Hodgkin Lymphoma). The use of routine imaging after a CR is being challenged by recent studies, so decisions regarding use can be made on an individual basis. A clear plan for surveillance is crucial, as timing of relapse has important prognostic significance and may impact treatment options. Early relapse (< 12 months) is a poor prognostic factor and warrants more aggressive therapy. Other prognostic factors include localized vs disseminated disease and disease that has relapsed in previously irradiated areas.
Management of Relapse Following Chemotherapy or CMT
HDCT + ASCT is the standard of care for relapsed/refractory classical Hodgkin lymphoma and can induce durable remissions in > 50% of patients. No randomized trials have compared the effectiveness of salvage regimens for classical Hodgkin lymphoma, so selecting the appropriate regimen may be a challenge when considering both efficacy and toxicities. Because the goal of salvage chemotherapy is to achieve a second CR, usually a regimen different from that used for the initial course of therapy is administered.
Some institutions favor platinum-based multidrug regimens, such as ICE (ifosfamide, carboplatin, and etoposide) or DHAP (dexamethasone, cytarabine, and cisplatin).[14,15] More recently, gemcitabine-based regimens[16,17] and the use of bendamustine have been explored; these regimens are effective and well tolerated even in heavily pretreated patients. Gemcitabine-based regimens have been used both as primary salvage and for secondary salvage after ASCT.[16,18,19] Few studies have been done comparing the efficacy of different multidrug regimens. A small prospective study of 44 patients compared GDP (gemcitabine, dexamethasone, and cisplatin) with ESHAP (etoposide, methylprednisolone, cisplatin, and cytarabine); no difference was found in the response rate for relapsed/refractory Hodgkin lymphoma.
Patients with relapsed or refractory disease after initial salvage have a median survival of < 3 years with standard therapies. Newer biologics and targeted therapies, such as brentuximab vedotin and nivolumab, may further improve survival. Brentuximab vedotin (SGN-35) is a CD30-directed antibody linked to monomethyl auristatin E, an antitubulin agent. In a phase I trial, this potent antibody-drug conjugate was able to induce a CR or PR in 17 of 45 patients with relapsed or refractory disease who had been treated with multiple prior therapies. The other 19 cases had stable disease after treatment. In a more recent multicenter, prospective, phase II study, the use of brentuximab enabled 86% of patients with relapsed/refractory Hodgkin lymphoma to proceed to ASCT. The conjugate has also been shown to be effective in patients with relapsed/refractory disease after prior autologous or allogeneic stem cell transplantation, with overall response rates of 75% and 50%, respectively.[24,25] Nivolumab is a programmed death 1 (PD-1)–blocking antibody that has considerable activity even in patients heavily pretreated for relapsed/refractory Hodgkin lymphoma who had previously failed brentuximab vedotin. Other targeted agents currently in development may also impact outcomes in the setting of relapsed/refractory classical Hodgkin lymphoma.
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