Novel Approaches for the Treatment of Classical HL

Siddhartha Ganguly, MD, FACP:I think we have come a long way since the 1960s, when we had radiotherapy, then developed MOPP [mechlorethamine, vincristine, procarbazine, prednisone], and then ABVD [doxorubicin, bleomycin, vinblastine, dacarbazine] had improved the outcome and decreased the toxicity. And then there was a big lull in the treatment of classic Hodgkin lymphoma until now, and now suddenly there’s an explosion of options that we have for treating patients with classic Hodgkin lymphoma. Besides brentuximab vedotin, I would like to mention that the PD-1 [programmed cell death protein 1] inhibitors have opened another gateway, another way to use immunotherapy in the treatment of this hematological malignancy.

In the beginning I said, yeah, 75% of the patients with classic Hodgkin lymphoma most likely would be cured with a modern therapy. But those 25% are not that lucky. And only 50% are salvageable by autologous stem cell transplantation. And even then, patients getting into the transplantation as PET2 [positron emission tomography]—negative fare much better than those transplanted with PET2-positive disease. Hence, we as physicians, oncologists, and transplanters should do our best to take the patients to the transplant and then keep the remission status as long as possible.

Going back to the ECHELON-1 study, of the patients who are given A-AVD [Adcetris, doxorubicin, vinblastine, dacarbazine], one-third fewer patients are requiring transplantation compared with the patients who received ABVD. I’m a transplanter, and I like to transplant. But I’m happy when my patients do not need my expertise. That means they are not relapsing or relapsing less to see a transplanter. And I think brentuximab vedotin has helped in some of those patients who do not need to go to the transplant. But for those patients who are required to go to transplantation, or relapse after transplantation, beyond brentuximab vedotin, I think we must recognize the role of the PD-1 and PD-L1 [programmed death-ligand 1].

To explain what PD-1 and PD-L1 antagonists do to us, when I was in medical school eons ago, I was always amazed looking at the cut section of a Hodgkin lymph node. Right in the middle is this large owl-eyed cancer cell looking back at me. And the cancer cell is surrounded by multiple inflammatory regulatory cells like macrophages, eosinophils, monocytes, and dendritic cells. I always wondered why this cancer cell is thriving amid a sea of killer cells. We did not realize it at that time, but now we know: there is a symbiosis going on. As I mentioned, CD30 and CD30 ligand—through these surrounding cells—maintain a nurturing environment by direct ligand or cytokine release. And the cells are nurtured by those mothering cells around the cancer cells.

On top of that, the Hodgkin Reed-Sternberg cell has a genetic predisposition to upregulate a segment of a chromosome called 9p24. And what 9p24 does is upregulate an antigen called PD-L1, which is programmed death ligand that interacts with the T-cells in the surrounding area through the programmed cell death receptor 1. And this interaction basically tells those T-cells that are surrounding the cancer cells not to come in and not to fight. This really sends a negative counter-regulatory stimulus for all the surrounding cells not to hurt the Reed-Sternberg cell. It is almost as if the cancer cells are wearing an armor and are surrounded by a moat so that all these inflammatory cells cannot reach them.

The drugs like nivolumab or pembrolizumab, which are the PD-1 antagonists, are blocking these negative counter-regulatory pathways, making chinks in the armor, and making the drawbridge drop, so the cancer cells are exposed to the surrounding environment of the T cells, which will just cross this moat, enter through the chinks in the armor or in the fortress, and kill the cancer cells. This is a very novel and exciting way of improving the response of refractory Hodgkin. The earlier studies show the single agent had an 87% overall response in relapsed-refractory Hodgkin, with around a 17% complete response.

One word of caution for PD-1 inhibitors, because it upregulates the T cells. Patients sometimes can present with symptoms like immune enhancement, like autoimmune. Patients may present with inflammation of the eyes, skin rash, diarrhea, pneumonitis. Of course, we know how to treat them with steroids, but one has to be vigilant. Another word of caution: patients with Hodgkin disease who are relapsed after autologous transplant, and we are contemplating the use of either single-agent nivolumab or pembrolizumab, or in combination with brentuximab vedotin, and then allogeneic stem cell transplantation, remember these drugs have a long half-life. And when the donor cells are introduced, the donor cells will find the body as foreign and will initiate graft vs. host disease. And now with the PD-1, PD-L1 antagonist in the system, graft versus host disease will be very much intensified, leading to exacerbation of graft versus host disease. One has to be very careful about selecting the donor, selecting the patient and the time interval, and how to take care of the increased risk of graft versus host disease.

Transcript edited for clarity.