Advances and Setbacks With Precision Medicine in Hodgkin Lymphoma, T-Cell Lymphomas

Allison J. Moskowitz, MD

Allison J. Moskowitz, MD

Brentuximab vedotin (Adcetris), an anti-CD30 antibody-drug conjugate, was approved by the FDA as treatment of patients with relapsed/refractory Hodgkin lymphoma (HL), based on data from the multicenter, randomized phase III ECHELON-1 clinical trial. The other approach to treating HL is with doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) therapy, based on findings from the phase III RATHL trial.

Patients who were randomized to receive brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) had an improved progression-free survival (PFS) compared to those who received the standard ABVD therapy in the ECHELON-1 study. In the RATHL study, patients experienced promising PFS and overall survival rates. ABVD therapy is the current standard of care in this setting, while A+AVD has not been universally adopted yet.

With these 2 treatments, HL is considered a highly curable disease, according to Allison J. Moskowitz, MD. Among these therapies, checkpoint inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) are also approved for the treatment of patients with HL who have already received at least 3 prior lines of therapy. However, because the first- and second-line therapies have such promising cure rates, most patients with HL will never need treatment with 1 of these immunotherapeutic agents.

In an interview withTargeted Oncology,Moskowitz, assistant attending, Lymphoma Service, Memorial Sloan Kettering Cancer Center, discussed the treatment options for patients with HL and what research is still to come in the field. She also compared the treatment landscape of HL with that of T-cell lymphomas, a rare subset of patients.

Targeted Oncology: Where do we stand with precision medicine in HL and T-cell lymphomas?

Moskowitz:For those 2 diseases, I think we stand in very different places. For HL, it is highly curable, so our goal of therapy is to maintain the cure rate, improve upon the cure rate, and also to reduce toxicity and long-term toxicity for patients. The role precision medicine can take in HL is to choose the right treatment for the right patient at the right time so that we are not overtreating patients or undertreating patients.

In T-cell lymphoma, we still have a lot of work to do because the prognosis in general for many of the entities is still unfavorable. We need new drugs and new targets so that we can develop new drugs for those targets. We also need new treatment approaches for some of the rarer entities in T-cell lymphoma so that we can make a difference in that disease.

Targeted Oncology: In HL, what is currently used to risk stratify patients?

Moskowitz:In the frontline setting for early-stage patients, certain risk factors are used to decide whether a patient hasfavorable disease or unfavorable disease. Those include factors such as whether or not they have B symptoms, an elevated ESR, bulky disease, and the number of sites of disease that they have. The problem with that risk stratification is that those risk factors are based upon patients who were treated with more historical treatments, such as outdated treatments. They haven’t been verified in our current modern therapies, so there is a lot of room for improvement there.

For advanced-stage disease, we have the International Prognostic Score, which has been looked at in modern therapy and is prognostic in patients receiving standard ABVD therapy. However, it is not doing a great job in distinguishing which patients are going to be the least favorable versus most favorable because there is not a huge difference between the highest risk group and the lowest risk group using that score.

Some risk factors that I think could make a difference is metabolic tumor volume, which is a way to measure how much tumor burden a patient has using the PET scan to measure that. That is prognostic in multiple different retrospective series, and now it’s being looked at retrospectively in prospective studies. Ongoing prospective studies are now incorporating this measurement in there so we can learn more about how we can use it to predict how a patient is going to do and how to choose therapy.

Another really exciting marker that I think is going to make a difference in HL is ctDNA, which enables us to not only look at the mutations within the patient’s tumor by looking at their blood, but this also may be a good marker for assessing responses to therapies. Reduction in ctDNA appears to be a very good marker to predict how a patient is going to do. However, more studies need to incorporate this into studies to figure out how we can use this in the future.

Targeted Oncology: In HL, what are the current approaches in the frontline setting?

Moskowitz:Two different common approaches are used here in the United States. The first is a PET-adapted approach, which is based on the RATHL study. The trial was focused on patients with more advanced stage disease, but patients started with 2 cycles of ABVD chemotherapy and were evaluated with a PET scan. If their PET scan is negative, it was found that it is safe to eliminate bleomycin with further treatment, so they only get 4 cycles of AVD therapy moving forward. If their PET scan is positive, the study escalated treatment, so incorporate escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escBEACOPP) for the rest of the treatment. It has been found that by incorporating escBEACOPP, the outcome for those patients at least appears better than what we expect compared to historical controls, but we don’t have randomized data to support that approach. However, it does look a little better.

Another approach is to treat with brentuximab vedotin with AVD, and that is based on the ECHELON-1 study. That study randomized patients between ABVD versus A+AVD. It did find there was a slightly higher PFS for the patients who received A+AVD versus ABVD. However, the reason this hasn’t beenadopteduniversally for patients is that the difference was not dramatic. Additionally, the side effects of A+AVD is a little more than we would see with ABVD, particularly with higher rates of neutropenic fever requiring every patient get growth factors with that regimenand also higher rates of peripheral neuropathy, which is what we would expect with brentuximab vedotin. On the other side, we do not get any pulmonary toxicities because we are eliminating bleomycin, but that is why it hasn’t been universally adopted. For higher-risk patients, it is not unreasonable to consider.

Targeted Oncology: What are targeted agents that are making head way?

Moskowitz:In HL, the other class of drugs that is so important is the checkpoint inhibitors, the PD-1 blockade. Both nivolumab and pembrolizumab are FDA-approved in the relapsed setting for HL, and now both of them are being evaluated in multiple other settings, including as maintenance therapy after transplant and in the first- and second-line settings. I don’t think, just like with A+AVD, these drugs should not be universally adapted for every patient, but I think that these studies are exciting. I think we will learn who the right patients are for these drugs in the future.

Targeted Oncology: How wide is the subset of patients that can receive the checkpoint inhibitors?

Moskowitz:Currently, the drugs are approved for patients who have relapsed after 3 lines of therapy. The majority of patients who are newly-diagnosed with HL will never see a checkpoint inhibitor because we have a good chance of curing them with the first-line therapy and a pretty good chance of curing them with the second-line therapy. However, the drugs are available otherwise for patients who have their disease come back after transplant or multiple lines of therapy.

Targeted Oncology: Looking at T-cell lymphoma, what are major challenges and coming excitement?

Moskowitz:T-cell lymphoma is lagging behind is because it is such a rare disease altogether. It represents about 20 different diseases under that umbrella of T-cell lymphoma, so each 1 of those diseases is very rare. It makes it very difficult to run clinical trials because it requires very broad collaboration internationally in order to allow enough patients on the study to get an idea of whether these drugs and treatment approaches are working. That has been 1 of the challenges, and of course, when it is a rare disease, it makes it more difficult to learn more about the important mutations and oncogenic drivers within those diseases. It is with a lot of great collaborations that we are learning more about these diseases and which targets may be relevant.