Immunotherapy in Hodgkin Lymphoma: Present Status and Future Strategies

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.

Optimizing outcomes in relapsed/refractory Hodgkin lymphoma: a review of current and forthcoming therapeutic strategies

“…Further details on the Checkmate 205, Keynote-087, ORIENT-1, and BGB-A317-203 trials have been provided elsewhere. 178 In conclusion, the Checkmate 205 and Keynote-087 phase II trials confirmed the high response rates, which were almost equally applicable in the prespecified different clinical circumstances of rr-cHL in terms of BV and ASCT pretreatment, as well as the well-tolerated side effects of checkpoint inhibitors. Furthermore, the midterm results confirm that responses can be durable.…”

“…However, the FDA has granted approval for patients with refractory HL, or who have relapsed after three or more lines of therapy, in both adult and pediatric populations. 178 Treatment with checkpoint inhibitors beyond conventionally defined progression. The unique mechanism of action of PD-1 inhibitors may permit the initial growth of the tumor.…”

“…212 Further details on CAR-T cells and other forms of immunotherapy as discussed in more detail elsewhere. 178 The role of allogeneic stem-cell transplantation in the era of novel agents Being, in the past, the only strategy with curative potential in rr-cHL, the role and the optimal timing of alloSCT have been questioned in the era of BV, and, especially, PD-1 inhibitors. Although patients who fail autoSCT now have improved outcomes, and a small minority may even be cured with novel agents, they still represent an unmet medical need.…”

Immune checkpoint inhibitors in patients with pretreated HodgkinÊs lymphoma: a Korean single-center, retrospective study

“…There are rare cases of immune checkpoint inhibitor-induced myocarditis [ 19 ]. As a result of recent data, in heavily pretreated disease, immune checkpoint inhibitors are moving to earlier lines of treatment [ 20 ].…”

Classical Hodgkin’s Lymphoma in the Era of Immune Checkpoint Inhibition

“…Disease progression of ~16 months in patients after pembrolizumab (anti–PD-1) treatment of refractory/relapsed cHL, though achieving an excellent response rate, indicated a non-durable long-term memory for anti-tumor immunologic response [31,106]. Consequently, patients need lifelong treatment until their disease progresses or unacceptable toxicity occur, however proposed for a time not exceeding 24 months [107]. Moreover, since, probably, some patients might gain benefit from a shorter treatment, research should investigate a strategy to select patients based on this aim.…”