Abstract
Although classical Hodgkin lymphoma (cHL) is usually curable, 20–30% of the patients experience treatment failure and most of them are typically treated with salvage chemotherapy and autologous stem cell transplantation (autoSCT). However, 45–55% of that subset further relapse or progress despite intensive treatment. At the advanced stage of the disease course, recently developed immunotherapeutic approaches have provided very promising results with prolonged remissions or disease stabilization in many patients. Brentuximab vedotin (BV) has been approved for patients with relapsed/refractory cHL (rr-cHL) who have failed autoSCT, as a consolidation after autoSCT in high-risk patients, as well as for patients who are ineligible for autoSCT or multiagent chemotherapy who have failed ≥ two treatment lines. However, except of the consolidation setting, 90–95% of the patients will progress and require further treatment. In this clinical setting, immune checkpoint inhibitors (CPIs) have produced impressive results. Both nivolumab and pembrolizumab have been approved for rr-cHL after autoSCT and BV failure, while pembrolizumab has also been licensed for transplant ineligible patients after BV failure. Other CPIs, sintilimab and tislelizumab, have been successfully tested in China, albeit in less heavily pretreated populations. Recent data suggest that the efficacy of CPIs may be augmented by hypomethylating agents, such as decitabine. As a result of their success in heavily pretreated disease, BV and CPIs are moving to earlier lines of treatment. BV was recently licensed by the FDA for the first-line treatment of stage III/IV Hodgkin lymphoma (HL) in combination with AVD (only stage IV according to the European Medicines Agency (EMA)). CPIs are currently being evaluated in combination with AVD in phase II trials of first-line treatment. The impact of BV and CPIs was also investigated in the setting of second-line salvage therapy. Finally, combinations of targeted therapies are under evaluation. Based on these exciting results, it appears reasonable to predict that an improvement in survival and a potential increase in the cure rates of cHL will soon become evident.
Highlights
Lymphoid malignancies were among the first to be cured with conventional chemotherapy.Campath-1H, an anti-CD52 monoclonal antibody, demonstrated significant activity in relapsed/refractory chronic lymphocytic leukemia in the 1990s [1,2], but immunotherapy revolutionized the treatment of lymphoid tumors with the introduction of the anti-CD20 moAb.rituximab, which was approved for relapsed/refractory low-grade lymphomas in the USA in 1997 and for follicular lymphomas in Europe in 1998 [3]
Following the outstanding results obtained in heavily pretreated classical Hodgkin lymphoma (HL) (cHL) in phase I trials with acceptable toxicity [122,123], nivolumab and pembrolizumab were further developed in the Checkmate
In 2016, Falchi et al published their experience on 10 patients, suggesting that treatment with nivolumab or pembrolizumab might result in higher complete remission (CR) rates, as observed in 5/5 patients who had been previously exposed to 5-azacitidine in the context of a phase one trial [145]
Summary
Lymphoid malignancies were among the first to be cured with conventional chemotherapy. Cancers 2019, 11, 1071 the beginning of the 21st century, when clear improvements were shown in the outcomes of first-line treatment of a variety of indolent and aggressive B-cell lymphomas [4,5,6,7,8,9,10,11,12,13,14] This great success, was not applicable to Hodgkin lymphoma (HL) at that time, as rituximab proved useful only in the rare subtype of nodular lymphocyte predominant HL (NLP-HL) [15], it still remains an off-label option even for this small subgroup. We will review the data on additional molecules and the potential role of the forthcoming chimeric antigen receptor-modified T-cell (CAR T-cell) technology in HL
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