Treating Newly-Diagnosed Hodgkin Lymphoma

Andrew Evens, DO, MSc, FACP, Associate Director for Clinical Services, Rutgers Cancer Institute of New Jersey, Medical Director, RWJBarnabas Health, New Brunswick, explains his approach to treating newly-diagnosed patients with Hodgkin Lymphoma.




Hi, my name is Dr. Andy Evans. I'm Associate Director of Clinical Services and director of the lymphoma program at the Rutgers Cancer Institute of New Jersey, and medical director of the oncology service line for RWJ Barnabas Health.

I recently gave a presentation at the ASH Annual Hematologic Malignancies Conference in September that is given every year on different hematologic malignancies. My topic was how I treat Hodgkin lymphoma.

I discussed a number of important topics at the ASH Hematologic Malignancies Meeting regarding Hodgkin lymphoma. It was mainly framed around newly‑diagnosed, classical Hodgkin lymphoma. We talked about early stage disease, advanced stage disease, and then also talked about older patients, which is a unique population of patients within Hodgkin lymphoma.

In early-stage Hodgkin lymphoma, the continuing discussion still today revolves around the decision-making process of whether the recommendation is for combined modality therapy—in other words, chemotherapy, followed by consolidative radiotherapy—or chemotherapy alone.

Like many things in oncology, there's not a right or a wrong. There have been a multitude of studies—3 large ones, randomized studies over the last few years—looking at PET‑adapted response for early-stage disease.

The hypothesis was, if you have an early negative PET scan after 2 cycles of ABVD, are you able to eliminate radiation as consolidation and not sacrifice the progression‑free survival or other acute end point.

All 3 studies show the same result, that even in early PET‑negativity, there still was an increased relapse rate in patients who did not receive radiation. In different studies, that ranged anywhere from 4%, upwards of 12%.

The one that showed 12% came out of the largest of those non‑inferiority studies from the EORTC H10 study. It was specifically in the subgroup called favorable Hodgkin lymphoma that has several lower‑risk features, not many sites of disease, normal sed rate, etc.

What it showed is there was a 12% increased risk in relapse in those patients. Now, there still can be the situation, counterbalanced against that, that there is a slight increased risk of late effects with radiation.

It still may be a younger patient with disease in her chest, etc., that you may want to still give chemotherapy alone.

How do I treat early stage Hodgkin's? I'll think about using the German Hodgkin's study criteria: 2 cycles of ABVD and 20 Gy of radiation for patients that have more peripheral disease, not in the chest. For most other patients, I am using chemotherapy alone. Usually, 4 cycles of ABVD, and acknowledging there may be a slight increase relapse rate, as alluded to.

We do know, however, there is not a difference in overall survival, which is an important factor in making that decision.

For advanced stage disease, there have been several important recent studies that have helped guide the decision-making process.

One also was response‑adapted, like early stage disease, that was called a RATHL study, response‑adapted therapy in Hodgkin lymphoma, done in Europe, led by Peter Johnson from the United Kingdom.

It also looked at early PET scan after 2 cycles of ABVD for advanced stage patients. It also included—by the way, we always think of that as an advanced stage study—40% of patients had unfavorable early stage, or early stage with adverse risk factors.

It really extrapolates also to that. For PET2‑negative, there was a randomization to drop the bleomycin. In other words, give AVD or continue ABVD, both for 6 cycles, and there was no difference between those 2 arms.

That is a valid option still in today's world, not just for advanced stage disease, but also for early stage unfavorable. For PET‑positive patients, they did change over to more intensified therapy with BEACOPP.

However, there was another, albeit smaller, study we conducted here in North America, initially published by the late Oli Press, the S0816 study, that we just updated recently by Dr. Stephens, et al., in Blood, published a few months ago.

That showed, with longer follow-up, at 5 years, even in PET2‑negative patients for advanced stage disease, that progression‑free survival is 76%. The early studies, when it looked at early PET negativity, we thought it was north of 90, 95%. It really just shows us that we still have room to improve upon.

Another breakthrough in the last couple years in the ECHELON‑1 study that added brentuximab vedotin to chemotherapy. The backbone is AVD chemotherapy.

The combination was that brentuximab vedotin chemotherapy versus standard ABVD. That was published almost 2 years ago in the New England Journal by Joe Connors, et al. That showed, at the high line study result, a 5% improvement in progression‑free survival. Modified, but also typical progression‑free survival.

That delta may seem small, but that equates to a relative risk reduction of approximately 23% in terms of progression‑free survival events. I think it's important, when looking at those study details, there were certain high‑risks group, whether a high Hasenclever prognostic score. Or even individual factors, such as stage four disease, extranodal disease, male gender, etc., where that delta or improvement was higher.

Also, a really intriguing subtext to that study were patients treated in North America had an absolute improvement of 12% in terms of progression‑free survival improvement when brentuximab vedotin was added.

We don't know exactly why. Was it supportive care? Was it other factors? That would equate to a number needed to treat of 8. In other words, 8 patients to treat to prevent 1 relapse, which is a little more palatable than, say, a number needed to treat of 20, which a 5% delta would give you.

Really, that represents a definite option for advanced stage Hodgkin's patients in general, but especially for high risk factors. Where are we current? Whereas the current or the future is a newly‑opened North American study for advanced stage Hodgkin's called S1826.

It literally is all of North America, number one. Number two, also the Children's Oncology Group is also collaborating on this. Patients 12 years and above will be enrolling to this study that is basically comparing the ECHELON‑1 backbone of brentuximab vedotin plus AVD, compared to a checkpoint inhibitor, nivolumab AVD therapy.

This study is open right now and accruing, and I definitely recommend you to consider that to open it at your local site for patients.

Finally, for older patients in Hodgkin lymphoma. Now, it's somewhat arbitrary that, when you use the age cutoff as 60 years and above, as many cancers have.

We've known for decades that older Hodgkin lymphoma patients have an inferior outcome. What's interesting, though, in Hodgkin lymphoma, that inferior outcome is more like 30, 40 percentage points worse in overall survival.

Why is that? We don't know exactly why. It's probably multiple reasons. Of course, older patients maybe aren't able to tolerate certain chemotherapy, and there are problems, we know, with bleomycin in older patients.

There is a definite increased risk of bleomycin lung toxicity. Also, there may be a slightly different disease. We see more mixed cellularity Hodgkin lymphoma, more Epstein‑Barr virus in the tumor itself.

All those factors probably lead to the poorer prognosis. There've been some recent studies, included from our group, where we also added brentuximab vedotin to chemotherapy, but we gave it sequentially, not concurrently, like the ECHELON‑1.

In other words, we started a newly‑diagnosed, older Hodgkin lymphoma patients with 2 cycles of brentuximab vedotin, almost as a window study and pre‑phase. Just from those 2 doses of brentuximab vedotin, the overall response rate was 87% and a complete remission rate of 30%.

Then patients went onto chemotherapy, 6 cycles of AVD, and then were consolidated with brentuximab vedotin. The other reason, besides giving a pre‑phase to improve patients' performance status, was also predicated on the tolerability.

We saw that, versus giving concurrent therapy, giving sequential, we saw much less neurotoxicity. At the end of the day, we were quite pleased to see a progression‑free survival rate in older patients almost comparable to younger patients, with progression‑free survival rate in the 80% range.


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