The use of personalized medicine in classical Hodgkin lymphoma continues to expand with the approval of immune checkpoint inhibitors that target PD-1, such as nivolumab and pembrolizumab, and antibody drug conjugates, such as brentuximab vedotin. Healio spoke with John Sweetenham, MD, FRCP, FACP, senior director of clinical affairs and executive medical director of Huntsman Cancer Institute at The University of Utah and HemOnc Today’s Chief Medical Editor for Hematology, about how these agents have changed the treatment paradigm for classical Hodgkin lymphoma and influenced ongoing research.
Question: How do genetic alterations contribute to the development and evolution of classical Hodgkin lymphoma?
Answer: In classical Hodgkin lymphoma, one of the most common genetic abnormalities that’s seen is either amplification or an increase in copy number of chromosome 9p24.1. This is an area on the chromosome that is known to code for what’s been known as the programmed-death 1 and programmed-death 2, or PD-1 and PD-2, ligands. These two ligands are important because expression of these two ligands has the effect of inhibiting T cells and effectively rendering the Hodgkin/Reed-Sternberg cell “invisible” to the immune system. It’s believed that part of the immune paresis that’s taking place in the microenvironment in Hodgkin lymphoma is because of the overexpression of these two ligands, PD-L1 and PD-L2, by the Hodgkin/Reed-Sternberg cells. The receptor for PD-L1 and PD-L2 is a receptor known as PD-1.
Question: How does this information affect prognosis and treatment?
Answer: The clinical significance of this genetic abnormality is that there are now monoclonal antibodies targeted to the PD-1 molecule on T cells. In essence, blocking the inhibitory effect of these two programmed-death ligands wakes up the immune system so that the Hodgkin/Reed-Sternberg cell is no longer invisible to infiltrating T cells in the microenvironment. As a result, it becomes subject to immune attack.
This chromosomal abnormality in classical Hodgkin lymphoma is highly significant. It’s been shown clearly that there is a correlation between amplification of this chromosome and this gene and prognosis. It has significance from a prognostic perspective and now, even more importantly, with the advent of checkpoint inhibitors such as pembrolizumab (Keytruda, Merck) and nivolumab (Opdivo, Bristol-Myers Squibb) that have shown great activity in Hodgkin lymphoma, it has real clinical significance as well.
Question: Where does brentuximab vedotin fit into the treatment landscape for classical Hodgkin lymphoma?
Answer: Brentuximab vedotin (Adcetris, Seattle Genetics), an antibody drug conjugate that targets CD30, is now widely used at various stages in the treatment of classical Hodgkin lymphoma. Initial trials of the drug were most often conducted among patients with relapsed or refractory disease, typically after one or two cycles of prior therapy and commonly after high-dose therapy and autologous stem cell transplant. The drug has demonstrated activity in many clinical settings in classical Hodgkin lymphoma. Perhaps the best-established settings at this point are as consolidation therapy for high-risk patients undergoing therapy and autologous stem cell transplant or patients whose disease has relapsed. In this context, the drug is used for 1 year after transplant as consolidation therapy and in patients known to be at high risk for relapse after transplant. This includes patients who initially had primary refractory disease, those who had an initial remission duration of less than 12 months or those who had extra-nodal disease at the time of relapse. In that group, there is clear evidence that, following transplant, PFS increases significantly with the use of consolidation therapy with brentuximab vedotin. It’s now a well-established standard of care.
This agent has also been widely used in the relapsed setting, both alone and in combination with other therapies. For example, single-agent brentuximab vedotin is sometimes used in patients who have relapsed after frontline chemotherapy. It’s used as cytoreductive therapy before these patients move on to a high-dose regimen. It may be combined with other, more conventional chemotherapies, such as the ICE combination, which consists of ifosfamide, carboplatin and etoposide.
More recently, there’s been interest in using brentuximab vedotin in the frontline treatment of patients with classical Hodgkin lymphoma. It’s been used as a single agent in this setting as well as in combination with other agents. The largest study in the combination setting is the ECHELON-1 trial. In this trial, patients with advanced classical Hodgkin lymphoma were randomly assigned to standard-of-care therapy with the ABVD regimen, which consists of doxorubicin, bleomycin, vincristine and dacarbazine, or a novel combination in which bleomycin from the ABVD regimen was substituted with brentuximab vedotin. That study is complete; it demonstrated an improvement in complete overall response rates in the brentuximab vedotin arm and a slight increase in modified PFS in favor of the brentuximab vedotin arm compared with the standard arm. The results of the ECHELON-1 trial are certainly interesting, although the value from a truly clinical/practical standpoint is still unclear, partly because there was an elevated risk of neutropenia in the brentuximab vedotin arm.
This is also partly true because, since the study began, the standard of care for classical Hodgkin lymphoma has changed as a result of the RATHL trial, which was published by researchers in the United Kingdom a couple of years ago. Now, it’s standard practice to omit bleomycin from the ABVD regimen in patients who respond well so that they only receive that drug for two cycles. Part of the initial rationale for substituting bleomycin for brentuximab vedotin was to reduce the risk of lung toxicity, but omitting bleomycin has a similar effect, so the true value of brentuximab vedotin in that frontline setting is not clear. Having said that, there are also some newer, more recent studies that have assessed sequential protocols with single-agent brentuximab vedotin given initially, followed by reduction in doses of ABVD or AVD. This approach is being used, increasingly, in older patients with Hodgkin lymphoma, where we know that the risks of lung toxicity from bleomycin are somewhat high.
Question: How is the treatment of classical Hodgkin lymphoma different in older patients?
Answer: In older patients with classical Hodgkin lymphoma, who are inconsistently defined as those aged 40 years and older or aged 50 years and older, one of the primary concerns is that outcomes appear somewhat worse than outcomes for younger patients. The other major concern is that older patients are more susceptible to toxicity from the ABVD regimen, specifically the lung toxicity related to bleomycin. These are two separate but possibly related issues – worse prognosis and increased toxicity.
As a result, a number of groups around the world have assessed different combinations of drug regimens for patients with classical Hodgkin lymphoma who are aged 40 years and older. There really are no standards of care in this context right now. An interesting approach that has developed in recent years is the use of lead-in brentuximab vedotin as a single agent. After 2 or 3 cycles with that therapy, a modified ABVD regimen is introduced, often with the omission of bleomycin. In some European studies, they’ve used other, more complex regimens, but still omitted bleomycin. These studies appear to show favorable outcomes in older patients, with reduced lung toxicity.
Question: What do these newer treatments indicate for the future of personalized medicine in classical Hodgkin lymphoma?
Answer: I think we are going to move into a new phase in classical Hodgkin lymphoma treatment that could, for some people, mean the complete omission of chemotherapy. There are already some clinical trials in development that are using chemotherapy-free induction regimens.
As we learn more about the role of amplification, for example, or gene copy alternations in 9p24.1, this may lead to a more personalized approach, similar to the use of checkpoint inhibitors in these patients. Similarly, although CD30 is widely present on Hodgkin/Reed-Sternberg cells, it gives us clues that there are certainly targets in classical Hodgkin lymphoma that can be specifically targeted with drugs without the need for chemotherapy. While chemotherapy for classical Hodgkin lymphoma has been extremely successful, and cure rates are high, these agents are still associated with significant toxicity. I think we’re going to see an increase in the use of targeted treatments. The choice of those targeted treatments will be based on the specific genetic or immunohistochemical characteristics of the Hodgkin/Reed-Sternberg cell in an individual patient. I think, initially, those treatments are most likely to be limited to the relapsed/refractory setting, but over time – and as we gain more confidence in these agents – I suspect we’ll see them increasingly brought into frontline therapy. Perhaps, at some point in the future, there will no longer be a need for chemotherapy in the treatment of this disease.
Disclosures: Sweetenham reports receiving honoraria from Seattle Genetics.
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