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Hodgkin's lymphoma: what is next in salvage treatment?

Current understanding of the nature of the Reed–Sternberg cell is now in accordance with a lymphocyte-activated cell, and the World Health Organization (WHO) classification has recommended the disease be classified as Hodgkin’s lymphoma (HL) [1], underlining the fact that therapeutic approaches can benefit from the progress made in other types of lymphoma. Three major advances have been made in the past 10 years in the treatment of HL. First, all HLs at diagnosis, even with localized stages, should be treated with chemotherapy, and the extent of radiotherapy fields, if any, are limited to involved sites or residual masses. Secondly, doxorubicin, vinblastine, bleomycin and dacarbazine (ABVD) is the standard chemotherapy regimen, not only because of its efficacy, but also due to its limited longterm toxicity. However, in poor prognosis patients, this regimen is now challenged with more intensive multidrug regimens such as bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (BEACOPP) [2]. This regimen, in a randomized study, did show significant benefit in terms of reduction of the incidence of early failure to initial chemotherapy, which was translated to a better event-free survival. The third area of progress in the treatment strategy has been intensification with autologous stem cell transplantation (ASCT) which could improve event-free survival in relapsing or refractory patients. Nevertheless, salvage chemotherapy has been of crucial importance in that setting as chemosensitivity is mandatory before transplantation for patients not achieving initial complete remission or relapsing. Prognostic factors affecting the outcome after salvage treatment have been studied extensively [3, 4]. Several factors are reproducible among studies, which have confirmed the adverse prognostic significance of the following: relapse at <12 months; disseminated stage; relapse in irradiated area; and B symptoms. The impact of positron emission tomography (PET) scans in the evaluation of failure is of increasing importance in distinguishing sclerotic residual masses from persisting disease in partial responders. Reports of the response rates for salvage regimens should be given according to these factors, as for relapses and induction failure it ranged from 50% to 90% with a 5-year probability of event-free survival ranging from 20% to 80%. Patients with at least two adverse prognostic factors have the worst survival. The same type of stratification should be adapted for treatment strategy, as reported by A. D. Zelenetz et al. for non-Hodgkin’s lymphoma in this issue. For patients without adverse factors (i.e. relapse in localized stage, not previously irradiated and without B symptoms) salvage chemotherapy with localized radiotherapy can cure 60% to 80% of patients. The other alternative is chemotherapy followed by ASCT which cured 80% of patients but might be associated with more long-term toxicity, although reports on second cancers with matched control patients failed to show a significant difference [5]. For patients experiencing early relapse or not achieving complete remission after first-line treatment the situation is more complex. Salvage chemotherapy regimens followed by ASCT can salvage only 20% of patients. The addition of radiotherapy with accelerated fractionated course with extended field before transplantation is an alternative that is not associated with an excess of second cancers [6]. Most investigators would rather use standard radiotherapy post-transplant on a limited field. In order to try to improve the poor results obtained, it has been proposed to introduce a second autotransplant, as reported by the Groupe d’Étude des Lymphomes de l’Adulte (GELA) in this issue, or for younger patients a non-myeloablative conditioning regimen followed by allogenic transplantation. All these procedures will need an effective salvage regimen to get the maximal tumor response before starting patients on these procedures. The design of a new salvage regimen should take in account several factors related to previous chemotherapy. Cumulative doses of drugs should be part of the decision in order to avoid or limit cumulative toxicity, such as cardiac toxicity with anthracyclines, or second cancer with alkylating agents or etoposide. The majority of chemotherapy agents should be composed of non-cross-resistant drugs and be able to be used with or without radiotherapy. Dose escalation should be studied with a range of dose effective regimens allowing mobilization of hematopoietic stem cells. In HL, the first effective regimen for salvage after mechlorethamine, vincristine, procarbazine and prednisone (MOPP) was ABVD, which was able to induce a >50% response rate. ABVD was then introduced as first-line treatment and numerous randomized studies demonstrated that tolerance was at least as good or even better than for MOPP, with less late effects. It now represents the standard first-line chemotherapy, although patients failing ABVD respond poorly to salvage therapy with MOPP, leading to a search for new salvage treatments. Regimens used in the salvage of non-Hodgkin’s lymphoma have often been tried, and response rates >50% have been reported with carmustine– etoposide–cytarabine–melphalan (mini-BEAM) and dexamethasone–BEAM (dexa-BEAM), as well as with dexamethasone– cisplatin–cytarabine (DHAP) and etoposide–high-dose cytarabine– cisplatin (ESHAP). However, those regimens have a cumulative