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To determine the optimal amount of treatment needed, there has been significant interest in using functional imaging to provide an early indication of chemosensitivity in HL. For patients with both favorable and unfavorable prognostic factors, noninferiority of ABVD only compared with combined modality treatment could not be demonstrated. The evidence therefore suggests that the use of combined modality treatment produces excellent disease control in patients with early stage HL, and that a high percentage of patients are cured with initial therapy.

The number needed to treat with radiation to achieve one extra cure is therefore between 15 and 30 based on these studies. In general, however, the outcomes with both approaches are excellent, and the small reduction in disease control does not appear to have any detrimental effect upon overall survival in either study. Since then, multiple other regimens have been developed in an attempt to improve on the efficacy of this regimen.

The ABVD chemotherapy regimen was then developed and also showed significant clinical activity with potentially less toxicity. The alternating regimen was found to be superior as regards the complete remission rate, freedom from progression, and overall survival. To further minimize toxicity, the Stanford V regimen was developed which incorporated the active agents from MOPP and ABVD into a brief dose intense regimen and combined this 12 week regimen with radiation therapy.

The differences in outcome however may be explained by the fact that the administration of radiotherapy in the Stanford V arm differed from what was originally described. Patients with residual or progressive disease were subsequently treated with salvage therapy including stem cell transplantation. The authors analyzed the outcome after initial therapy and also after salvage therapy. These results have led some to suggest that initial therapy may not need to be highly aggressive in all patients as those who relapse may be salvaged with subsequent intensive therapy.

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Patients with a persistently positive PET scan came off study and received salvage therapy. The conclusion from this arm of the study was that the omission of bleomycin from the ABVD regimen after a negative interim PET scan resulted in a lower incidence of pulmonary toxicity than seen with continued ABVD, but not significantly lower efficacy.

To potentially further improve the outcome of advanced HL patients with poor prognostic features, the role of high dose chemotherapy HDCT with autologous stem cell transplantation ASCT has been evaluated as part of initial therapy for these patients. The strategies discussed above have largely focused on intensification of therapy to improve the outcome of patients with advanced stage Hodgkin lymphoma.

A more recent approach has been to add novel agents to standard chemotherapy regimens. Novel agents currently being used in combination with chemotherapy in the frontline setting include brentuximab vedotin, rituximab, and lenalidomide. Brentuximab vedotin was initially combined with ABVD, and subsequently substituted for bleomycin, in a phase I study. However, significant pulmonary toxicity was seen when brentuximab vedotin was administered in combination with bleomycin resulting in the concurrent use of bleomycin and brentuximab vedotin being contraindicated.

Neutropenia, infections and peripheral neuropathy were more common in the brentuximab vedotin plus AVD arm, while pulmonary toxicity was more frequent with ABVD. Both studies demonstrated high complete response rates and the event free survival in both studies suggested promising activity of this combination. The efficacy of this combination, however, will need to be confirmed in a randomized trial.

However, dose intense regimens such as escalated BEACOPP should be considered in patients with advanced disease and multiple poor prognostic factors. In the future, the addition of novel agents to established combinations may result in improved outcomes for HL patients. An exception to the management approach outlined above are early stage patients with nodular lymphocyte predominant HL.

More advanced stage patients with nodular lymphocyte predominant HL are commonly treated with ABVD, often in combination with rituximab because the malignant cells express CD Clinical trials are in progress to define the optimal therapy for this disease. Patients with primary refractory disease, defined as progression or nonresponse during induction treatment or within 90 days of completing treatment, generally have a dismal clinical course. A number of retrospective analyses have suggested that patients treated with ASCT have a superior long term outcome when compared to patients treated with chemotherapy.

Despite the responses to these therapeutic approaches, however, patients relapse and subsequently die of disease progression or complications of treatment. Most eligible patients with relapsed disease are now treated with an autologous stem cell transplant. Not all patients are eligible for, or may benefit from, an ASCT. Patients were included if they had unfavorable risk factors defined as primary refractory disease, progression within 12 months of an initial response to frontline therapy, or extranodal involvement prior to salvage therapy. The median PFS was Patients with progression of disease after ASCT uniformly have a poor outcome.

Among cytotoxic drugs, only vinorelbine 89 and gemcitabine 90 have shown promising activity in heavily pretreated HL patients, including some cases who relapsed after HDCT. The duration of many of the responses however was short and the treatment was commonly associated with significant hematological toxicity. Phase I and II clinical trials of brentuximab vedotin, an antibody to CD30 conjugated to an antitubulin agent auristatin, showed significant clinical activity. The median duration of response was 47 weeks and the agent was relatively well tolerated. In an initial clinical trial using nivolumab, 23 patients with relapsed and refractory Hodgkin lymphoma received nivolumab every other week.

This patient cohort was also heavily pretreated with the majority of patients previously receiving an autologous stem cell transplant or brentuximab vedotin. Confirmatory phase 2 studies have been performed in Hodgkin lymphoma using both pembrolizumab and nivolumab. The response rate seen with pembrolizumab were similar in patients with primary refractory disease to those relapsing after multiple lines of therapy. Other agents with promising activity in this patient population include histone deacetylase HDAC inhibitors, mTOR inhibitors and immunomodulatory agents.

The median duration of response was 6. The median PFS was 9 months. Optimal management of patients with HL requires an accurate diagnosis and careful staging of the disease. Future directions to further improve the outcome of patients with HL will include incorporating into frontline therapy additional agents that are effective in the relapsed setting.


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